Tetracyclic derivatives, process of preparation and use

ABSTRACT

A compound of formula (I)  
                 
 
     and salts and solvates thereof, in which:  
     R o  represents hydrogen, halogen or C 1-6  alkyl;  
     R 1  represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6  alkynyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-3 alkyl, arylC 1-3 alkyl or heteroaryl C 1-3 alkyl;  
     R 2  represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring  
                 
 
      attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and  
     R 3  represents hydrogen or C 1-3  alkyl, or R 1  and R 3  together represent a 3- or 4-membered alkyl or alkenyl chain.  
     A compound of formula (I) is a potent and&#39;selective inhibitor of cyclic guanosine 3′, 5′-monophosphate specific phosphodiesterase (CGMP specific PDE) having a utility in a variety of therapeutic areas where such inhibition is beneficial, including the treatment of cardiovascular disorders.

[0001] This invention relates to a series of tetracyclic derivatives, toprocesses for their preparation, pharmaceutical compositions containingthem, and their use as therapeutic agents. In particular, the inventionrelates to tetracyclic derivatives which are potent and selectiveinhibitors of cyclic guanosine 3′, 5′-monophosphate specificphosphodiesterase (CGMP specific PDE) having utility l in a variety oftherapeutic areas where such inhibition is thought to be beneficial,including the treatment of cardiovascular disorders.

[0002] Thus, according to a first aspect, the present invention providescompounds of formula (I)

[0003] and salts and solvates (e.g. hydrates) thereof, in which:

[0004] RO represents hydrogen, halogen or C₁₋₆ alkyl;

[0005] R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,haloC₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₃alkyl, arylC₁₋₃alkyl orheteroarylC₁₋₃alkyl;

[0006] R² represents an optionally substituted monocyclic aromatic ringselected from benzene, thiophene, furan and pyridine or an optionallysubstituted bicyclic ring

[0007] attached to the rest of the molecule via one of the benzene ringcarbon atoms and wherein the fused ring A is a 5- or 6-membered ringwhich may be saturated or partially or fully unsaturated and comprisescarbon atoms and optionally one or two heteroatoms selected from oxygen,sulphur and nitrogen; and

[0008] R³ represents hydrogen or C₁₋₃ alkyl, or R¹ and R³ togetherrepresent a 3- or 4-membered alkyl or alkenyl chain.

[0009] There is further provided by the present invention a subgroup ofcompounds of formula (I), the subgroup comprising compounds of formula(Ia)

[0010] and salts and solvates (e.g. hydrates) thereof, in which:

[0011] R^(o) represents hydrogen, halogen or C₁₋₆ alkyl;

[0012] R¹ represents hydrogen, C₁₋₆alkyl, halo C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₃alkyl, arylC₁₋₃alkyl orheteroarylC₁₋₃alkyl; and

[0013] R² represents an optionally substituted monocyclic aromatic ringselected from benzene, thiophene, furan and pyridine or an optionallysubstituted bicyclic ring

[0014] attached to the rest of the molecule via one of the benzene ringcarbon atoms and wherein the fused ring A is a 5- or 6-membered ringwhich may be saturated or partially or fully unsaturated and comprisescarbon atoms and optionally one or two heteroatoms selected from oxygen,sulphur and nitrogen.

[0015] Within R¹ above, the term “aryl” as part of an arylC₁₋₃alkylgroup means phenyl or phenyl substituted by one or more (e.g. 1, 2 or 3)substituents selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy andmethylenedioxy. The term “heteroaryl” as part of a heteroarylC₁₋₃alkylgroup means thienyl, furyl or pyridyl each optionally substituted by oneor more (e.g. 1, 2 or 3) substituents selected from halogen, C₁₋₆ alkyland C₁₋₆alkoxy. The term “C₃₋₈cycloalkyl” as a group or part of aC₃₋₈cycloalkylC₁₋₃alkyl group means a monocyclic ring comprising threeto eight carbon atoms. Examples of suitable cycloalkyl rings include theC₃₋₆cycloalkyl rings cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

[0016] Within R² above, optional benzene ring substituents are selectedfrom one or more (e.g. 1, 2 or 3) atoms or groups comprising halogen,hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, -CO₂R^(b), halo C₁₋₆alkyl, haloC₁₋₆alkoxy, cyano, nitro and NR^(a)R^(b), where R^(a) and R^(b) are eachhydrogen or C₁₋₆alkyl, or R^(a) may also represent C₂₋₇alkanoyl orC₁₋₆alkylsulphonyl. Optional substituents for the remaining ring systemsare selected from one or more (e.g. 1, 2 or 3) atoms or groupscomprising halogen, C₁₋₆alkyl, C₁₋₆alkoxy and arylC₁₋₃alkyl as definedabove. The bicyclic ring

[0017] may, for example, represent naphthalene, a heterocycle such asbenzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline,indole, benzothiophene or benzofuran or

[0018] (where n is an integer 1 or 2 and X and Y may each represent CH₂,O, S or NH).

[0019] In the above definitions, the term “alkyl” as a group or part ofa group means a straight chain or, where available, a branched chainalkyl moiety. For example, it may represent a C₁₋₄alkyl function asrepresented by methyl, ethyl, n-propyl, i-propyl, n-butyl, s-utyl andt-butyl. The term ‘alkenyl’ as used herein includes straight-chained andbranched alkenyl groups, such as vinyl and allyl groups. The term‘alkynyl’ as used herein includes straight-chained and branched alkynylgroups, suitably acetylene. The term “halogen” herein means a fluorine,chlorine, bromine or iodine atom. The term “haloC₁₋₆alkyl” means analkyl group as defined above comprising one to six carbon atomssubstituted at one or more carbon atoms by one or more (e.g. 1, 2 or 3)halogen atoms. Similarly, a halo C₁₋₆alkoxy group is a halo C₁₋₆alkylgroup as defined above linked to the R² benzene ring via an oxygen atom.Examples of haloC₁₋₆alkyl groups include trifluoromethyl and2,2,2-trifluoroethyl. An example of a halo C₁₋₆alkoxy group istrifluoromethoxy. The term “C₂₋₇alkanoyl” means a C₁₋₆alkylcarbonylgroup where the C₁₋₆alkyl portion is as defined above. An example of asuitable C₂₋₇alkanoyl group is the C₂alkanoyl group acetyl.

[0020] It will be appreciated that when R^(o) is a halogen atom or aC₁₋₆alkyl group this substituent may be sited at any available positionon the phenyl portion of the tetracyclic ring. However, a particularsite of attachment is the ring 10-position.

[0021] The compounds of formula (I) may contain two or more asymmetriccentres and thus can exist as enantiomers or diastereoisomers. Inparticular, in formula (I) above two ring chiral centres are denotedwith asterisks. It is to be understood that the invention includes bothmixtures and separate individual isomers of the compounds of formula(I).

[0022] The compounds of formula (I) may also exist in tautomeric formsand the invention includes both mixtures and separate individualtautomers thereof.

[0023] The pharmaceutically acceptable salts of the compounds of formula(I) which contain a basic centre are acid addition salts formed withpharmaceutically acceptable acids. Examples include the hydrochloride,hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulphonate, benzenesulphonate andp-toluenesulphonate salts. Compounds of the formula (I) can also providepharmaceutically acceptable metal salts, in particular alkali metalsalts, with bases. Examples include the sodium and potassium salts.

[0024] A particular group of compounds of the invention are thosecompounds of formula (I) in which R^(o) is hydrogen or halogen (e.g.fluorine), especially hydrogen.

[0025] Another particular group of compounds of the invention are thosecompounds of formula (I) in which R¹ represents hydrogen, C₁₋₄alkyl,haloC₁₋₄alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylmethyl, pyridylC₁₋₃alkyl,furylC₁₋₃alkyl or optionally substituted benzyl. Within this particulargroup of compounds, examples of C₁₋₄alkyl groups are methyl, ethyl,n-propyl, i-propyl and n-butyl. Examples of C₃₋₆cycloalkylmethyl groupsare cyclopropylmethyl and cyclohexylmethyl. Examples of optionallysubstituted, benzyl groups include benzyl and halobenzyl (e.g.fluorobenzyl).

[0026] A further particular group of compounds of the invention arethose compounds of formula (I) in which R² represents an optionallysubstituted benzene, thiophene, furan, pyridine or naphthalene ring oran optionally substituted bicyclic ring

[0027] (where n is 1 or 2 and X and Y are each CH₂ or O). Within thisparticular group of compounds, examples of substituted benzene groupsare benzene substituted by one of halogen (e.g. chlorine), hydroxy,C₁₋₃alkyl (e.g. methyl, ethyl or i-propyl), C₁₋₃alkoxy (e.g. methoxy orethoxy), —CO₂R^(b), halomethyl (e.g. trifluoromethyl), halomethoxy (e.g.trifluoromethoxy), cyano, nitro or NR^(a)R^(b) where R^(a) and R^(b) areeach hydrogen or methyl or R^(a) is acetyl; or benzene substituted bydihalo (e.g. dichloro) or by C₁₋₃alkoxy (e.g. methoxy) and one ofhalogen (e.g. chlorine) and hydroxy. An example of a substitutedthiophene ring is a halo (e.g. bromo) substituent thiophene ring.

[0028] A still further particular group of compounds of formula I arethose wherein R³ represents hydrogen or R¹ and R³ together represent a3-membered alkyl chain.

[0029] A preferred group of compounds of the invention are the cisisomers of formula (I) represented by formula (Ib)

[0030] and mixtures thereof with their cis optical enantiomers,including racemic mixtures, and salts and solvates (e.g. hydrates) ofthese compounds in which R^(o) is hydrogen or halogen (e.g. fluorine),especially hydrogen and R¹ R² and R³ are as defined previously.

[0031] The single isomers represented by formula (Ib), i.e. the 6R, 12aRisomers, are particularly preferred.

[0032] Within the above definitions R¹ may preferably representC₁₋₄alkyl (e.g. methyl, ethyl, i-propyl and n-butyl), C₃₋₆cycloalkyl(e.g. cyclopentyl) or C₃₋₆cycloalkylmethyl (e.g. cyclopropylmethyl).

[0033] R² may preferably represent a substituted benzene ring such asbenzene substituted by C₁₋₃alkoxy (e.g. methoxy) or by C₁₋₃alkoxy (e.g.methoxy) and halogen (e.g. chlorine), particularly 4methoxyphenyl or3-chloro4-methoxyphenyl, or R² may preferably represent3,4-methylenedioxyphenyl.

[0034] It is to be understood that the present invention covers allappropriate combinations of particular and preferred groupingshereinabove.

[0035] Particular individual compounds of the invention include:

[0036]Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0037]Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5yl)-2methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0038]Cis-2,3,6,7,12,12a-hexahydro-6-(-5-bromo-2-thienyl)-2methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0039]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-]indole-1,4-dione;

[0040] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0041] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione;

[0042] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0043] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0044] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;

[0045] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b] indole-1,4-dione;

[0046] (5aR, 12R,14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5-1,4-dione;

[0047] and physiologically acceptable salts and solvates (e.g. hydrates)thereof.

[0048] A specific compound of the invention is:

[0049] (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-]indole-1,4-dione;

[0050] and physiologically acceptable salts and solvates (e.g. hydrates)thereof.

[0051] It has been shown that compounds of the present invention arepotent and selective inhibitors of cGMP specific PDE. Thus, compounds offormula (I) are of interest for use in therapy, specifically for thetreatment of a variety of conditions where inhibition of cGMP specificPDE is thought to be beneficial.

[0052] As a consequence of the selective PDE V inhibition exhibited bycompounds of the present invention, cGMP levels are elevated, which inturn can give rise to beneficial anti-platelet, anti-neutrophil,anti-vasospastic, vasodilatory, natriuretic and diuretic activities aswell as potentiation of the effects of endothelium-derived relaxingfactor (EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brainnatriuretic peptide (BNP), C-type natriuretic peptide (CNP) andendothelium-dependent relaxing agents such as bradykinin, acetylcholineand 5-HT₁. The compounds of formula (I) therefore have utility in thetreatment of a number of disorders, including stable, unstable andvariant (Prinzmetal) angina, hypertension, pulmonary hypertension,congestive heart failure, renal failure, atherosclerosis, conditions ofreduced blood vessel patency (e.g. post-percutaneous transluminalcoronary angioplasty), peripheral vascular disease, vascular disorderssuch as Raynaud's disease, inflammatory diseases, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, glaucoma anddiseases characterised by disorders of gut motility (e.g. irritablebowel syndrome).

[0053] It will be appreciated that references herein to treatment extendto prophylaxis as well as treatment of established conditions.

[0054] It will also be appreciated that ′a compound of formula (I),′ ora physiologically acceptable salt or solvate thereof can be administeredas the raw compound, or as a pharmaceutical composition containingeither entity.

[0055] There is thus provided as a further aspect of the invention acompound of formula (I) for use in the treatment of stable, unstable andvariant (Prinzmetal) angina, hypertension, pulmonary hypertension,chronic obstructive pulmonary disease, congestive heart failure, renalfailure, atherosclerosis, conditions of reduced blood vessel patency,(e.g. post-PTCA), peripheral vascular disease, vascular disorders suchas Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronicasthma, allergic asthma, allergic rhinitis, glaucoma or diseasescharacterised by disorders of gut motility (e.g. IBS).

[0056] According to another aspect of the invention, there is providedthe use of a compound of formula (I) for the manufacture of a medicamentfor the treatment of stable, unstable and variant (Prinzmetal) angina,hypertension, pulmonary hypertension, chronic obstructive pulmonarydisease, congestive heart failure, renal failure, atherosclerosis,conditions of reduced blood vessel patency, (e.g. post-PTCA), peripheralvascular disease, vascular disorders such as Raynaud's disease,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma or diseases characterised bydisorders of gut motility (e.g. IBS).

[0057] In a further aspect, the invention provides a method of treatingstable, unstable and variant (Prinzmetal) angina, hypertension,pulmonary hypertension, chronic obstructive pulmonary disease,congestive heart failure, renal failure, atherosclerosis, conditions ofreduced blood vessel patency, (e.g. post-PTCA), peripheral vasculardisease, vascular disorders such as Raynaud's disease, inflammatorydiseases, stroke, bronchitis, chronic asthma, allergic asthma, allergicrhinitis, glaucoma or diseases characterised by disorders of gutmotility (e.g. IBS) in a human or non-human animal body which comprisesadministering to said body a therapeutically effective amount of acompound with formula (I).

[0058] Compounds of the invention may be administered by any suitableroute, for example by oral, buccal, sub-lingual, rectal, vaginal, nasal,topical or parenteral (including intravenous, intramuscular,subcutaneous and intracoronary) administration. Oral administration isgenerally preferred.

[0059] For administration to man in the curative or prophylactictreatment of the disorders identified above, oral dosages of a compoundof formula (I) will generally be in the range of from 0.5-800 mg dailyfor an average adult patient (70 kg). Thus for a typical adult patient,individual tablets or capsules contain from 0.2-400 mg of activecompound, in a suitable pharmaceutically acceptable vehicle or carrier,for administration in single or multiple doses, once or several timesper day. Dosages for intravenous, buccal or sublingual administrationwill typically be within the range of from 0.1-400 mg per single dose asrequired. In practice the physician will determine the actual dosingregimen which will be most suitable for an individual patient and itwill vary with the age, weight and response of the particular patient.The above dosages are exemplary of the average case but there can beindividual instances in which higher or lower dosage ranges may bemerited, and such are within the scope of this invention. For human use,a compound of the formula (I) can be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, the compound may beadministered orally, buccally or sublingually, in the form of tabletscontaining excipients such as starch or lactose, or in capsules orovules either alone or in admixture with excipients, or in the form ofelixirs or suspensions containing flavouring or colouring agents. Suchliquid preparations may be prepared with pharmaceutically acceptableadditives such as suspending agents (e.g. methylcellulose, asemi-synthetic glyceride such as witepsol or mixtures of glycerides suchas a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8and caprylic/capric glycerides). A compound may also be injectedparenterally, for example intravenously, intramuscularly, subcutaneouslyor intracoronarily. For parenteral administration, the compound is bestused in the form of a sterile aqueous solution which may contain othersubstances, for example salts, or monosaccharides such as mannitol orglucose, to make the solution isotonic with blood.

[0060] Thus, the invention provides in a further aspect a pharmaceuticalcomposition comprising a compound of the formula (I) together with apharmaceutically acceptable diluent or carrier therefor.

[0061] There is further provided by the present invention a process ofpreparing a pharmaceutical composition comprising a compound of formula(I), which process comprises mixing a compound of formula (I) togetherwith a pharmaceutically acceptable diluent or carrier therefor.

[0062] A compound of formula (I) may also be used in combination withother therapeutic agents which may be useful in the treatment of theabove-mentioned disease states. The invention thus provides, in anotheraspect a combination of a compound of formula (I) together with anothertherapeutically active agent.

[0063] The combination referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical compositions comprising a combination as defined abovetogether with a pharmaceutically acceptable diluent or carrier comprisea further aspect of the invention.

[0064] The individual components of such a combination may also beadministered either sequentially or simultaneously in separatepharmaceutical formulations.

[0065] Appropriate doses of known therapeutic agents for use incombination with a compound of formula (I) will be readily appreciatedby those skilled in the art.

[0066] Compounds of formula (I) may be prepared by any suitable methodknown in the art or by the following processes which form part of thepresent invention. In the methods below R^(o), R¹ and R² are as definedin formula (I) above unless otherwise indicated.

[0067] Thus, a process (A) for preparing a compound of formula (I)wherein R³ represents hydrogen comprises treating a compound of formula(II)

[0068] (in which Alk represents C₁₋₆alkyl, e.g. methyl or ethyl and Halis a halogen atom, e.g. chlorine) with a primary amine R¹NH₂ in asuitable solvent such as an alcohol (e.g. methanol or ethanol) or amixture of solvents, conveniently at a temperature of from 20° C. toreflux (e.g. at about 50° C.).

[0069] A compound of formula (II) may conveniently be prepared bytreating a compound of formula (III)

[0070] with a haloacetyl halide (e.g. chloroacetyl chloride) in asuitable solvent such as a halogenated hydrocarbon (e.g.trichloromethane or dichloromethane), or an ether (e.g.tetrahydrofuran), preferably in the presence of a base such as anorganic amine (e.g. a trialkylamine such as triethylamine) or an alkalimetal carbonate or bicarbonate (e.g. NaHCO₃). The reaction mayconveniently be effected at a temperature of from −20° C. to +20° C.(e.g. at about 0° C.).

[0071] A compound of formula (I) may also be prepared from a compound offormula (III) in a two-step procedure via a compound of formula (II)isolated without purification.

[0072] Compounds of formula (I) may be prepared as individualenantiomers in two steps from the appropriate enantiomer of formula(III) or as mixtures (e.g. racemates) of either pairs of cis or transisomers from the corresponding mixtures of either pairs of cis or transisomers of formula (III).

[0073] Individual enantiomers of the compounds of the invention may beprepared from racemates by resolution using methods known in the art forthe separation of racemic mixtures into their constituent enantiomers,for example using HPLC (high performance liquid chromatography) on achiral column such as Hypersil naphthylurea.

[0074] A compound of formula (III) may conveniently be prepared from atryptophan alkyl ester of formula (IV)

[0075] (where Alk is as previously defined) or a salt thereof (e.g. thehydrochloride salt) according to either of the following procedures (a)and (b). Procedure (b) is only suitable for preparing cis i of formula(III) and may be particularly suitable for preparing individual cisenantiomers of formula (III) from D- or L-tryptophan alkyl esters asappropriate.

[0076] Procedure (a)

[0077] This comprises a Pictet-Spengler cyclisation between a compoundof formula (IV) and an aldehyde R²CHO. The reaction may conveniently beeffected in a suitable solvent such as a halogenated hydrocarbon (e.g.dichloromethane) or an aromatic hydrocarbon (e.g. toluene) in thepresence of an acid such as trifluoroacetic acid. The reaction mayconveniently be carried out at a temperature of from −20° C. to refluxto provide a compound of formula (III) in one step. The reaction mayalso be carried out in a solvent such as an aromatic hydrocarbon (e.g.benzene or toluene) under reflux, optionally using a Dean-Starkapparatus to trap the water produced.

[0078] The reaction provides a mixture of cis and trans isomers whichmay be either individual enantiomers or racemates of pairs of cis ortrans isomers depending upon whether racemic or enantiomerically puretryptophan alkyl ester was used as the starting material. Individual cisor trans enantiomers may conveniently be separated from mixtures thereofby fractional crystallisation or by chromatography (e.g. flash columnchromatography) using appropriate solvents and eluents. Similarly, pairsof cis and trans isomers may be separated by chromatography (e.g. flashcolumn chromatography) using appropriate eluents. An optically puretrans isomer may also be converted to an optically pure cis isomer usingsuitable epimerisation procedures. One such procedure comprises treatingthe trans isomer or a mixture (e.g. 1:1 mixture) of cis and transisomers with methanolic or aqueous hydrogen chloride at a temperature offrom 0° C. to the refluxing temperature of the solution. The mixture maythen be subjected to chromatography (e.g. flash column chromatography)to separate the resulting diastereoisomers, or in the procedureutilising aqueous hydrogen chloride the desired cis isomer precipitatesout as the hydrochloride salt which may then be isolated by filtration.

[0079] Procedure (b)

[0080] This comprises a four-step procedure from a compound of formula(IV) or a salt thereof (e.g. the hydrochloride salt). The procedure isparticularly suitable for preparing a 1R, 3R isomer of formula (III)from a D-tryptophan alkyl ester of formula (IV) or a salt thereof (e.g.the hydrochloride salt). Thus, a first step (i) comprises treating acompound of formula (IV) with an acid halide R²COHal (where Hal is aspreviously defined) in the presence of a base, e.g. an organic base suchas a trialkylamine (for example triethylamine), to provide a compound offormula (V)

[0081] The reaction may be conveniently carried out in a suitablesolvent such as a halogenated hydrocarbon (e.g. dichloromethane) or anether (e.g. tetrahydrofuran) and at a temperature of from −20° C. to+40° C.

[0082] Step (ii) comprises treating a compound of formula (V) with anagent to convert the amide group to a thioamide group. Suitablesulfurating agents are well-known in the art. Thus, for example, thereaction may conveniently be effected by treating (V) with Lawesson'sreagent. This reaction may conveniently be carried out in a suitablesolvent such as an ether (e.g. dimethoxyethane) or an aromatichydrocarbon (e.g. toluene) at an elevated temperature such as from 40°C. to 80° C. to provide a compound of formula (VI)

[0083] Step (iii) comprises treating a compound of formula (VI) with asuitable agent to provide a compound of formula (VII)

[0084] (where Hal is a halogen atom, e.g. iodine). The reaction mayconveniently be effected by treating (VI) with an alkylating agent suchas a methyl halide (e.g. methyl iodide) or an acylating agent such as anacetyl halide (e.g. acetyl chloride) in a suitable solvent such as ahalogenated hydrocarbon (e.g. dichloromethane) at an elevatedtemperature (e.g. under reflux).

[0085] In step (iv) the resulting iminium halide of formula (VII) may betreated with a reducing agent such as boron hydride, e.g. sodiumborohydride, to provide the desired compound of formula (III). Thereduction may conveniently be effected at a low temperature, e.g. withinthe range of −100° C. to 0° C., in a suitable solvent such as an alcohol(e.g. methanol).

[0086] There is further provided by the present invention a process (B)for preparing a compound of formula (I), wherein R¹ and R³ togetherrepresent a 3- or 4-membered alkyl or alkenyl chain, which process (B)comprises cyclisation of a compound of formula (VII)

[0087] wherein Alk represents C₁₋₆alkyl and R¹ and R³ together representa 3- or 4-membered chain both as hereinbefore described. The cyclisationis suitably carried out in an organic solvent or solvents, such as analcoholic solvent (e.g. methanol) and optionally an ether solvent suchas tetrahydrofuran, and in the presence of a reducing agent, aptly apalladium catalyst, such as palladium on carbon.

[0088] Conveniently a compound of formula (VIII) is prepared by reactionof a compound of formula (III) as hereinbefore described with a compoundof formula (IX)

[0089] wherein Hal represents a halogen atom as hereinbefore described,R¹ and R³ together represent a 3- or 4-membered chain as hereinbeforedescribed and R⁴ represents a protecting group, suitably abenzyloxycarbonyl group or the like. Typically the reaction is carriedout in a chlorinated organic solvent, such as dichloromethane, and atertiary amine, such as triethylamine or the like.

[0090] According to a further aspect of the present invention, there isprovided a process (C) for preparing a compound of formula (I) whereinR³ represents C₁₋₃alkyl, which process comprises cyclisation of acompound of formula (X)

[0091] wherein Alk represents C₁₋₆alkyl as hereinbefore described and R⁵represents C₂₋₅salkyl, substituted at C₁ by a halogen atom, the halogenatom being as hereinbefore described. Suitably the cyclisabon isachieved by reflux for many hours, such as 22 to 26 hours, in thepresence of an ether solvent, such as tetrahydrofuran, and a suitableamine as hereinafter described in the accompanying examples.

[0092] Aptly a compound of formula (X) can be prepared from a compoundof formula (III) by suitable acylation techniques, such as reaction witha C₃₋₆carboxylic acid, substituted at C₂ by a halogen atom in ahalogenated organic solvent, such as dichloromethane.

[0093] Compounds of formula (I) may be converted to other compounds offormula (I). Thus, for example, when R² is a substituted benzene ring itmay be necessary or desirable to prepare the suitably substitutedcompound of formula (I) subsequent to process (A), (B) or (C) as above.Examples of appropriate interconversions include nitro to amino oraralkyloxy to hydroxy by suitable reducing means (e.g. using a reducingagent such as SnCl₂ or a palladium catalyst, such aspalladium-on-carbon), or amino to substituted amino such as acylamino orsulphonylamino using standard acylating or sulphonylating conditions. Inthe case where R² represents a substituted bicyclic system, suitableinterconversion can involve removal of a substituent, such as bytreatment with a palladium catalyst (e.g. palladium-on-carbon) whereby,for example, a benzyl substituent may be removed from a suitablebicyclic system.

[0094] The pharmaceutically acceptable acid addition salts of thecompounds of formula (I) which contain a basic centre may be prepared ina conventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of a compound of formula (I) with a suitable base. Both typesof salt may be formed or interconverted using ion-exchange resintechniques.

[0095] Compounds of the invention may be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent.

[0096] Thus, according to a further aspect of the invention, we providea process for preparing a compound of formula (I) or a salt or solvate(e.g. hydrate) thereof which comprises process (A), (B) or (C) ashereinbefore described followed by

[0097] i) an interconversion step; and/or either

[0098] ii) salt formation; or

[0099] iii) solvate (e.g. hydrate) formation.

[0100] There is further provided by the present invention compounds offormulae (II), (VIII), (X) and further compounds of formulae (III), (V),(VI) and (VII), with the exception for compounds (III), (V), (VI) and(VII) wherein R^(o) is hydrogen, R² is phenyl and Alk is methyl.

[0101] The synthesis of the compounds of the invention and of theintermediates for use therein are illustrated by the following,non-limiting Examples. In the Examples section hereinafter the followingabbreviations are used:

[0102] DMSO (dimethylsulphoxide), MeOH (methanol), EtOH (ethanol), DMF(dimethylformamide), EtOAc (ethyl acetate) and THF (tetrahydrofuran).

[0103] Intermediates 1 and 2

[0104] Methyl1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0105] To a stirred solution of racemic tryptophan methyl ester (13 g)and piperonal (9.7 g) in anhydrous CH₂Cl₂ (300 mL) cooled at 0° C. wasadded dropwise trifluoroacetic acid (9 mL) and the solution was allowedto react at ambient temperature. After 4 days, the yellow solution wasdiluted with CH₂Cl₂ (100 mL), washed with a saturated aqueous solutionof NaHCO₃, then with water and dried over Na₂SO₄. The organic layer wasevaporated to dryness under reduced pressure and the residue waspurified by flash chromatography eluting with CH₂Cl₂/MeOH (99/1) to givefirst Intermediate 1, the cis isomer (6.5 g) m.p. 90-93° C. followed byIntermediate 2, the trans isomer (6.4 g) m.p.: 170° C. The followingcompounds were obtained in a similar manner:

[0106] Intermediates 3 and 4

[0107] Methyl1,2,3,4-tetrahydro-1-(4-ethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0108] The same method but starting from racemic tryptophan methyl esterand 4-methoxybenzaldehyde gave Intermediate 3, the cis isomer as whitecrystals m.p.: 142° C. and Intermediate 4, the trans isomer as whitecrystals m.p.: 209-210° C.

[0109] Intermediate 5

[0110] Methyl1,2,3,4-tetrahydro-1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer

[0111] The same method but starting from racemic tryptophan methyl esterand 3-methoxybenzaldehyde gave the title compound as white crystalsm.p.: 146° C.

[0112] Intermediates 6 and 7

[0113] Methyl1,2,3,4-tetrahydro-1-(4-ethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0114] The same method but starting from racemic tryptophan methyl esterand 4-ethoxybenzaldehyde gave Intermediate 6, the cis isomer as whitecrystals m.p.: 180° C. and Intermediate 7, the trans isomer as whitecrystals m.p.: 196-198° C.

[0115] Intermediates 8 and 9

[0116] Methyl1,2,3,4-tetrahydro-1-(2,3-dihydrobenzo[b]furan-5yl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0117] The same method but starting from racemic tryptophan methyl esterand 2,3-dihydrobenzo[b]furan-5-carboxaldehyde gave Intermediate 8, thecis isomer as white crystals m.p.: 106-109° C. and Intermediate 9, thetrans isomer as white crystals m.p.: 219-222° C.

[0118] Intermediates 10 and 11

[0119] Methyl1,2,3,4-tetrahydro-1-(3,4-ethylenedioxyphenyl-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers The same method but starting from racemictryptophan methyl ester and 1,4-benzodioxancrboxaldehyde gaveIntermediate 10, the cis isomer as white crystals m.p.: 104-106° C. andIntermediate 11, the trans isomer as white crystals m.p.: 207-209° C.

[0120] Intermediate 12

[0121] Methyl1,2,3,4-tetrahydro-1-(2-chlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Mixture of Cis and Trans Isomers

[0122] The same method but starting from racemic tryptophan methyl esterand 2-chlorobenzaldehyde gave the title compound as white crystals m.p.:154° C.

[0123] Intermediates 13 and 14

[0124] Methyl1,2,3,4-tetrahydro-1-(4-chlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0125] The same method but starting from racemic tryptophan methyl esterand 4-2, chlorobenzaldehyde gave Intermediate 13, the cis isomer aswhite crystals m.p. : 208-209° C. and Intermediate 14, the trans isomeras white crystals m.p.: 108-109° C.

[0126] Intermediates 15 and 16

[0127] Methyl1,2,3,4-tetrahydro-1-(3,4-dichlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0128] The same method but starting from racemic tryptophan methyl esterand 3,4-dichlorobenzaldehyde gave Intermediate 15, the cis isomer as awhite solid ¹H NMR (CDCl₃)δ(ppm): 7.8-7 (m, 8H, H aromatic); 5.15 (brs,1H, H-1);3.9-3.8(dd, 1H, H-3)3.7(s, 3H, CO₂CH₃);3.2-3.1(ddd, 1H,H4)2.9(m, 1H, H-4); 2.4(brs, 1H, NH) and Intermediate 16, the transisomer as a white solid m.p.: 204° C.

[0129] Intermediate 17

[0130] Methyl1,2,3,4-tetrahydro-1-(1,2,3,4-tetrahydro-6-naphthyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer

[0131] The same method but starting from racemic tryptophan methyl esterand 1,2,3,4-tetrahydronaphthyl-6-carboxaldehyde gave the title compoundas a white solid ¹H NMR (CDCl₃)δ(ppm): 7.7-7(m, 8H, H aromatic); 5.2 (s,1H, H-1); 4.0 (dd, 1H, H-3); 3.8 (s, 3H, CO₂CH₃); 3.2 (m, 1H. H-4); 3.0(m, 1H, H-4); 2.7 (m, 4H, CH₂Ar);1.7 (s, 4H, CH₂CH₂Ar).

[0132] Intermediates 18 and 19

[0133] Methyl1,2,3,4-tetrahydro-1-(2-naphthyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0134] The same method but starting from racemic tryptophan methyl esterand 2-naphthaldehyde gave Intermediate 18, the cis isomer as a whitesolid ¹H NMR (CDCl₃)δ(ppm): 8-6.9 (m, 12H, H aromatic); 5.4 (s, 1H,H-1); 3.95 (dd, 1H, H-3);3.7(s, 3H, CO₂CH₃)3.2(ddd, 1H, H-4);3(m, 1H,H4);2.5(brs, 1H, NH) and Intermediate 19, the trans isomer as a whitesolid (0.6 g) m.p.: 119° C.

[0135] Intermediates 20 and 21

[0136] Methyl1,2,3,4-tetrahydro-1-(2-thienyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0137] The same method but starting from racemic tryptophan methyl esterand 2-thiophenecarboxaldehyde gave Intermediate 20, the cis isomer as apale yellow solid m.p.: 134-137° C. and Intermediate 21, the transisomer as white crystals m.p.: 169° C.

[0138] Intermediates 22 and 23

[0139] Ethyl1,2,3,4-tetrahydro-1-(3-thienyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0140] The same method but starting from racemic tryptophan ethyl esterand 3-thiophenecarboxaldehyde gave Intermediate 22, the cis isomer aswhite crystals m.p.: 130° C. and Intermediate 23, the trans isomer aswhite crystals m.p.: 182-184° C.

[0141] Intermediates 24 and 25

[0142] Methyl1,2,3,4-tetrahydro-1-(5-bromo-2-thienyl)-9H-pyrido[3,4-b]indole-carboxylate,Cis and Trans Isomers

[0143] The same method but starting from racemic tryptophan methyl esterand 5-bromo-2-thiophenecarboxaldehyde gave Intermediate 24, the cisisomer as a cream solid m.p.: 130° C. and Intermediate 25, the transisomer as a cream solid m.p.: 205° C.

[0144] Intermediates 26 and 27

[0145] Methyl1,2,3,4-tetrahydro-1-(4-bromo-2-thienyl))-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0146] The same method but starting from racemic tryptophan methyl esterand 4-bromo-2-thiophenecarboxaldehyde gave Intermediate 26, the cisisomer as a cream solid m.p.: 200° C. and Intermediate 27, the transisomer as a cream solid m.p.: 120° C.

[0147] Intermediate 28

[0148] Methyl1,2,3,4-tetrahydro-1-(3-furyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Mixture of Cis and Trans Isomers

[0149] The same method but starting from racemic tryptophan methyl esterand 3-furaldehyde gave the title compound as a yellow solid m.p.: 130°C.

[0150] Intermediates 29 and 30

[0151] Ethyl1,2,3,4-tetrahydro-1-(5-methyl-2-furyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0152] The same method but starting from racemic tryptophan ethyl esterand 5-methylfurfural gave Intermediate 29, the cis isomer as a oilycompound ¹H NMR (CDCl₃)δ(ppm): 7.7 (brs, 1H, NH indole); 7.5 (d, 1 H, Haromatic); 7.25-6.9 (m, 3H, H aromatic); 6.15 (d, 1H, H aromatic); 5.85(m, 1H, H aromatic); 5.25 (brs, 1H, H-1); 4.2 (q, 2H, CO₂CH₂CH₃); 3.8(dd, 1H, H-3); 3.2-2.8 (m, 2H, H4); 2.2 (s, 3H, CH₃); 1.25 (t, 3H,CO₂CH₂CH₃) and Intermediate 30, the trans isomer as a cream solid m.p.:152° C.

[0153] Intermediates 31 and 32

[0154] Ethyl1,2,3,4-tetrahydro-1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0155] The same method but starting from racemic tryptophan ethyl esterand p-tolualdehyde gave Intermediate 31, the cis isomer as whitecrystals m.p.: 148° C. and Intermediate 32, the trans isomer as whitecrystals m.p.: 180° C.

[0156] Intermediates 33 and 34

[0157] Methyl1,2,3,4-tetrahydro-1-(3-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0158] The same method but starting from racemic tryptophan methyl esterand m-tolualdehyde gave Intermediate 33, the cis isomer as whitecrystals ¹H NMR (CDCl₃) δ(ppm): 7.6-7 (m, 9H, H aromatic); 5.2 (brs, 1H,H-1); 4-3.9 (dd, 1H, H-3) 3.8 (s, 3H, CO₂CH₃); 3.2-3.1 (ddd, 1H, H-4) 3(m, 1H, H-4); 2.35 (s, 3H, CH₃); 1.7 (brs, 1H, NH) and Intermediate 34,the trans isomer as a white solid m.p.: 175° C.

[0159] Intermediates 35 and 36

[0160] Methyl1,2,3,4-tetrahydro-1-(4-trifluoromethylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0161] The same method but starting from racemic tryptophan methyl esterand 4-trifluoromethylbenzaldehyde gave Intermediate 35, the cis isomeras pale yellow crystals m.p.: 190° C. and Intermediate 36, the transisomer as pale yellow crystals m.p.: 203° C.

[0162] Intermediates 37 and 38

[0163] Ethyl1,2,3,4-tetrahydro-1-4-cyanophenyl)-9H-pyrido[3,4-b]indol-3-carboxylate,Cis and Trans Isomers

[0164] The same method but starting from racemic tryptophan ethyl esterand 4-cyanobenzaldehyde gave Intermediate 37, the cis isomer as whitecrystals m.p.: 200° C. and Intermediate 38, the trans isomer as whitecrystals m.p.: 156° C.

[0165] Intermediate 39

[0166] Methyl1,2,3,4-tetrahydro-1-(4-hydroxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer

[0167] The same method but starting from racemic tryptophan ethyl esterand 4-hydroxybenzaldehyde gave the title compound as pale yellowcrystals ¹H NMR (DMSO) δ(ppm): 10.3 (s, 1H, NH-indole) 9.4 (s, 1H, OH);7.8-7.5 (m, 8H, H aromatic); 5.1 (brs, 1H, H-1); 3.9 (m, 1H, H-3); 3.75(s, 3H, CO₂CH₃) 3.1 (m, 1H, H-4); 2.8 (m, 1H, H4).

[0168] Intermediate 40

[0169] Methyl1,2,3,4-tetrahydro-1-(3-hydroxy-4-methoxyphenyl)9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer

[0170] The same method but starting from racemic tryptophan methyl esterand 3-hydroxy-4-methoxybenzaldehyde gave the title compound as a yellowsolid m.p.: 140-148° C.

[0171] Intermediate 41

[0172] Methyl1,2,3,4-tetrahydro-1-(4-hydroxy-3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer

[0173] The same method but starting from racemic tryptophan methyl esterand 4-hydroxy-3-methoxybenzaldehyde gave the title compound as a creamsolid m.p.: 195° C.

[0174] Intermediate 42

[0175] Methyl1,2,3,4-tetrahydro-1-(4-ethylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0176] The same method but starting from racemic tryptophan methyl esterand 4-ethylbenzaldehyde gave the cis and trans isomer of the titlecompound. Cis isomer: white solid ¹H NMR (CDCl₃) δ(ppm): 7.65-7.1 (m,9H, H aromatic); 5.25 (brs, 1H, H-1); 4(dd, 1H, H-3); 3.9 (s, 3H,CO₂CH₃); 3.4 (ddd, 1H, H-4); 3.1 (m, 1H, H-4); 2.7 (q, 2H, CH₂CH₃) 1.4(t, 3H, CH₂CH₃). Trans isomer: white solid m.p.: 187° C.

[0177] Intermediates 43 and 44

[0178] Methyl1,2,3,4-tetrahydro-1-(4-isopropylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0179] The same method but starting from racemic tryptophan ethyl esterand 4-isopropylbenzaldehyde gave Intermediate 43, the cis isomer as awhite solid ¹H NMR (DMSO) δ(ppm): 10.15 (s, 1H, NH indole); 7.3-6.7 (m,8H, H aromatic); 5 (brs, 1H, H-1); 3.6 (m, 1H, H-3); 3.5 (s, 3H,CO₂CH₃); 2.95-2.5 (m, 3H, H-4+CH-(Me)₂) 2.4 (brs, 1H, NH); 1(d, 6H,2xCH₃) and Intermediate 44, the trans isomer as a white solid m.p.: 189°C.

[0180] Intermediates 45 and 46

[0181] Ethyl1,2,3,4-tetrahydro-1(4-nitrophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0182] The same method but starting from racemic tryptophan ethyl esterand 4-nitrobenzaldehyde gave Intermediate 45, the cis isomer as yellowcrystals m.p.: 168° C. and Intermediate 46, the trans isomer as yellowcrystals m.p.: 195° C.

[0183] Intermediate 47

[0184] Ethyl1,2,3,4-tetrahydro-1-(4-dimethylaminophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Mixture of Cis and Trans Isomers

[0185] The same method but starting from racemic tryptophan ethyl esterand 4-dimethylaminobenzaldehyde gave the title compound as whitecrystals m.p.: 170° C.

[0186] Intermediates 48 and 49

[0187] Ethyl1,2,3,4-tetrahydro-1-(3-pyridyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0188] The same method but starting from racemic tryptophan ethyl esterand 3-pyridinecarboxaldehyde gave Intermediate 48, the cis isomer aspale yellow crystals m.p.: 230-232° C. and Intermediate 49, the transisomer as white crystals m.p.: 210-214° C.

[0189] Intermediates 50 and 51

[0190] Methyl 1,2,3,4tetrahydro-6-fluoro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0191] The same method but starting from racemic 5-fluoro-tryptophanmethyl ester and piperonal gave Intermediate 50, the cis isomer as acream solid m.p.: 60° C. and Intermediate 51, the trans isomer as acream solid m.p.: 213° C.

[0192] Intermediates 52 and 53

[0193] Methyl1,2,3,4-tetrahydro-6-fluoro-1-(4-methoxyphenyl)-9H-pyrido[3,4b]indole-3-carboxylate,Cis and Trans Isomers

[0194] The same method but starting from racemic 5-fluoro-tryptophanmethyl ester and 4-methoxybenzaldehyde gave Intermediate 52, the cisisomer as a solid 1H NMR (CDCl₃) δ (ppm): 7.4-6.8 (m, 8H, H aromatic);5.15 (brs, 1H, H-1); 3.9 (dd, 1H, H-3) 3.8 (s, 3H, CO₂CH₃); 3.2-2.9 (m,2H, H4) and Intermediate 53, the trans isomer as a Solid m.p.: 197° C.

[0195] Intermediates 54 and 55

[0196] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,cis isomer and

[0197] (1S,3R)-methyl1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylateTrans Isomer

[0198] To a stirred solution of D-tryptophan methyl ester (11 g) andpiperonal (7.9 g) in anhydrous CH₂Cl₂ (400 mL) cooled at 0° C. was addeddropwise trifluoroacetic acid (7.7 mL) and the solution was allowed toreact at ambient temperature. After 4 days, the yellow solution wasdiluted with CH₂Cl₂ (200 mL) and washed with a saturated aqueoussolution of NaHCO3, then with water (3×200 mL) and dried over Na₂SO₄.The organic layer was evaporated under reduced pressure and the residuewas purified by flash chromatography eluting with dichloromethane/ethylacetate (97/3) to give first Intermediate 54, the cis isomer (6.5 g)m.p.: 154° C. followed by Intermediate 55, the trans isomer (8.4 g)m.p.: 188° C.

[0199] The following compounds were obtained in a similar manner:

[0200] Intermediate 56

[0201] (1S, 3S)Methyl-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer and

[0202] (1R, 3S)methyl-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Trans Isomer

[0203] The same method but starting from L-tryptophan methyl ester andpiperonal gave the cis and trans isomers of the title compound.

[0204] Cis isomer: white crystals m.p.: 154° C.

[0205] Trans isomer: white crystals m.p.: 187-189° C.

[0206] Intermediates 57 and 58

[0207] (1R, 3R)Methyl1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3carboxylate,Cis Isomer and

[0208] (1S,3R)-methyl1,2,2,3,4-tetrahydro-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Trans Isomer

[0209] The same method but starting from D-tryptophan methyl ester and4-methoxybenzaldehyde gave Intermediate 57, the cis isomer as whitecrystals m.p.: 124-125° C. and Intermediate 58, trans isomer as whitecrystals m.p. 219-222° C.

[0210] Intermediates 59 and 60

[0211] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(3chloro-4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3carboxylate,Cis Isomer and

[0212] (1S, 3R)-methyl 1,2,3,4-tetrahydro-1-(3-chloro-4-methoxyphenyl)9H-pyrido[3,4-b]indole-3-carboxylate, Trans Isomer

[0213] The same method, but starting from D-tryptophan methyl ester and3-chloro-4-methoxybenzaldehyde gave Intermediate 59, the cis isomerisolated as the hydrochloride salt as white crystals m.p.: 200° C. andIntermediate 60, the trans isomer as white crystals m.p.: 164° C.

[0214] Intermediates 61 and 62

[0215] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(2,3-dihydrobenzo[b]furan-5-yl)-9H-pyrido[3,4-b]indole-3-carboxylate,cis isomer and

[0216] (1S, 3R)-methyl 1,2,3,4-tetrahydro-1-(5-(2,3dihydrobenzo[b]furan))-9H-pyrido[3,4-b]indole-3-carboxylate, TransIsomer

[0217] The same method but starting from D-tryptophan methyl ester and2,3-dihydrobenzo[b]furan-5-carboxaldehyde gave Intermediate 61, the cisisomer as white crystals m.p.: 282° C. and Intermediate 62, the transisomer as white crystals m.p. 204° C.

[0218] Intermediates 63 and 64

[0219] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(5-indanyl-9H-pyridof[3,4-b]indole-3-carboxylateCis Isomer and

[0220] (1S,3R)-methyl1,2,3,4-tetrahydro-1-(5-indanyl)-9H-pyrido[3,4-b]indole-3-carboxylateTrans Isomer

[0221] The same method but starting from D-tryptophan methyl ester andindan-5-carboxaldehyde gave Intermediate 63, the cis isomer as whitecrystals m.p.: 130-131° C. and Intermediate 64, the trans isomer aswhite crystals m.p.: 196° C.

[0222] Intermediate 65

[0223] Ethyl1,2,3,4-tetrahydro-1-(4-trifluoromethoxyphenyl-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0224] The same method but starting from racemic tryptophan ethyl esterand 4-trifluoromethoxybenzaldehyde gave cis and trans isomers of thetitle compound.

[0225] Cis isomer: white crystals m.p.: 88° C.

[0226] Trans isomer: white crystals m.p.: 152° C.

[0227] Intermediate 66

[0228] Methyl 1,2,3,4-tetrahydro-1-(5-methyl-2-thienyl)-9H-pyrido[3,4-b]indole-3-carboxylate, Cis and Trans Isomers

[0229] The same method but starting from racemic tryptophan methyl esterand 5-methyl-2-thiophenecarboxaldehyde gave the cis and trans isomers ofthe title compound.

[0230] Cis isomer: oily compound ¹H NMR (CDCl₃) δ (ppm): 8.4 (brs, 1H,NH-indole); 7.7-6.6 (m, 6H, H aromatic); 5.5 (brs, 1H, H-1); 3.9 (dd,1H, H-3); 3.85 (s, 3H, CO₂CH₃); 3.3-2.9 (m, 2H, H-4); 2.5 (s, 3H, CH₃).

[0231] Trans isomer: white crystals m.p.: 194° C.

[0232] Intermediates 67 and 68

[0233] (1S,3R)-Methyl1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylateand

[0234] (1R, 3R)-methyl1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0235] To a stirred solution of D-tryptophan methyl ester (obtained bytreating the corresponding hydrochloride salt in water with saturatedaqueous NaHCO₃ solution and extraction with CH₂Cl₂) (25.7 g) andpiperonal (19.4 g) in anhydrous dichloromethane (700 ml) cooled to 0° C.was added dropwise trifluoroacetic acid (18.1 ml) and the solution wasallowed to react at 4° C. After 5 days, the yellow solution was dilutedwith dichloromethane (500 ml). The organic layer was washed with asaturated aqueous solution of NaHCO3, then with water (3×500 ml) untilthe pH was neutral and dried over Na₂SO₄. The organic layer wasevaporated under reduced pressure to a volume of about 500 ml. Thetrans-isomer, which crystallised, was filtered and the filtrate wasreduced to 200 ml.

[0236] Another fraction of the trans-isomer crystallised. The fractionsof trans-isomer were combined to give the (1S,3R) isomer, Intermediate67, as white crystals (11.4 g).

[0237] mp: 188° C.

[0238] [α]_(D) ^(20°)=+32.4° (c=1.03, CHCl₃).

[0239] The filtrate containing mainly the cis-isomer was reduced to 100ml and isopropyl ether (200 ml) was added. Upon cooling, the (1R, 3R)isomer, Intermediate 68, crystallised as a white solid (17.4 g).

[0240] mp: 154-155° C.

[0241] [α]_(D) ^(20°)=+24.4° (c=1.03, CHCl₃).

[0242] Intermediate 69

[0243] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-3,4-methylenedioxyohenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0244] Method A

[0245] Intermediate 67 (5.0 g) was dissolved in methanol (150 ml).Hydrogen chloride was bubbled into the solution for several minutes at0° C. and the resulting yellow solution was refluxed for 24 hours. Thesolvent was removed under reduced pressure and the residue was basifiedwith a saturated aqueous solution of NaHCO₃ and extracted withdichloromethane. The organic layer was washed with water, dried overNa₂SO₄ and purified by flash chromatography eluting withdichloromethanelmethanol (99/1) to give the title compound (2.3 g)corresponding to an authentic sample of Intermediate 68.

[0246] Method B

[0247] Intermediate 67 (25 g) was heated in 1N hydrochloric acid (78.5ml) and water (400 ml) at 60° C. for 36 hours. From the initial paleyellow solution, a white solid precipitated. The mixture was thenallowed to cool to 0° C. and the solid filtered. The solid was thenwashed with diisopropyl ether (3×200 ml) and dried to give thehydrochloride salt of the title compound (20 g) as a white solid.

[0248] mp (dec.): 209-212° C.

[0249] Method C A 1:1 mixture of the cis and trans isomers ofIntermediates 54 and 55 (2 g) was heated in 1N hydrochloric acid (6.8ml) and water (15 ml) at 50° C. for 72 hours. A similar work-up asdescribed in Method B above gave the hydrochloride salt of the titlecompound (1.7 g) as a white solid.

[0250] Intermediate 70

[0251] (R)-N^(α)-(3,4-Methylenedioxyphenylcarbonyl)-tryptophan MethylEster

[0252] To a suspension of D-tryptophan methyl ester hydrochloride (10.2g) in anhydrous CH₂Cl₂ (150 ml) cooled at 0° C. was added dropwisetriethylamine (12.3 ml). To the resulting solution solid piperonyloylchloride (8.16 g) was added portionwise at the same temperature, and themixture was stirred at room temperature for 2 h. The mixture was washedsuccessively with water, 0.5N hydrochloric acid, water, a saturatedaqueous solution of NaHCO₃ and again with water. After drying overNa₂SO₄ and evaporation of the solvent under reduced pressure, theresulting oil on trituration from hot cyclohexane afforded the titlecompound as a white solid (14.7 g).

[0253] mp: 123-124° C.

[0254] [α]_(D) ^(20°)=−84.40° (c=1.04, CHCl₃).

[0255] Intermediate 71

[0256] (R)-N^(α)-(3,4-Methylenedioxyphenylthiocarbonyl)-troptophanMethyl Ester

[0257] A mixture of Intermediate 70 (14 g) and Lawesson's reagent (9.28g) in dimethoxyethane (280 ml) was heated at 60° C. under N₂ for 16hours with stirring. The reaction mixture was evaporated to dryness andthe resulting oil was dissolved in ethyl acetate, then washedsuccessively with an aqueous saturated solution of NaHCO₃ and water anddried over Na₂SO₄. The oily residue obtained after evaporation underreduced pressure gave, on trituration from cyclohexane, a yellow powderwhich was filtered and washed with cooled methanol to afford the titlecompound (9.74 g).

[0258] mp: 129-130° C.

[0259] [α]_(D) ^(20 °)=−186.8° (c=1.14, CHCl₃).

[0260] Intermediate 72

[0261] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0262] A solution of Intermediate 71 (9 g) and methyl iodide (10 ml) inanhydrous dichloromethane (200 ml) was heated at reflux under an argonatmosphere with protection from light. After 24 hours, the solvent wasremoved under reduced pressure to give an orange oil which ontrituration from hexane gave a solid which was washed with ether andused without further purification in the next step. This compound (13.11g) was dissolved in methanol (250 ml) and the solution was cooled to−78° C. NaBH₄ (0.99 g) was then added by portions and the mixture wasstirred at the same temperature for 1 hour. The reaction was quenched byaddition of acetone (10 ml) and the solvent was removed under reducedpressure. The residue was dissolved in CH₂Cl₂, washed with water andthen with brine and dried over Na₂SO₄. After evaporation of the solvent,the orange oil gave on trituration from a hot mixture of diethylether/cyclohexane an orange powder which was recrystallised from diethyletheripentane to afford the title compound as a pale yellow solid (5.15g) corresponding to an authentic sample of Intermediate 68.

[0263] Intermediate 73

[0264] (1R, 3R)-Methyl1,2,3,4-tetrahydro-2-chloroacetyl-(3,4-methylenedioxyphenyl-9H-pyrido[3,4-b]indole-3-carboxylate

[0265] Method A

[0266] To a stirred solution of Intermediate 72 (9.7 g) and NaHCO₃ (2.79g) in anhydrous CHCl₃ (200 ml) was added dropwise chloroacetyl chloride(5.3 ml) at 0° C. under N₂. The resulting mixture was stirred for 1 hourat the same temperature and diluted with CHCl₃ (100 ml). Water (100 ml)was then added dropwise with stirring to the mixture, followed by asaturated aqueous solution of NaHCO₃. The organic layer was washed withwater until neutrality and dried over Na₂SO₄. After evaporation of thesolvent under reduced pressure, the oily compound obtained wascrystallised from ether to give the title compound as a pale yellowsolid (9.95 g).

[0267] mp: 233° C.

[0268] [α]_(D) ^(20°)=−125.4°(c=1.17, CHCl₃).

[0269] Method B Chloroacetyl chloride (4 ml) was added dropwide to asolution of Intermediate 72 (16.1 g) and triethylamine (7 ml) inanhydrous CH₂Cl₂ (200 ml) at 0° C. under N₂. The solution was stirred at0° C. for 30 minutes, then diluted with CH₂Cl₂ (300 ml). The solutionwas washed with water (200 ml), a saturated aqueous solution of NaHCO₃(300 ml) and brine (400 ml). After drying over Na₂SO₄ and evaporationunder reduced pressure, the resulting solid was washed with ether (300ml) to give the title compound as a pale yellow solid (18.3 g).

[0270] Intermediate 74

[0271] Methyl1,2,3,4-tetrahydro-6-methyl-1-(3,4-methylenedioxyphenyl-9H-pyrido[3,4-b]indole-3-carboxylate,Cis and Trans Isomers

[0272] The cis and trans isomers of the title compound were preparedusing the method described in Intermediate 1 but starting from racemic5-methyl-tryptophan methyl ester and piperonal.

[0273] Cis isomer: yellow solid m.p.: 85° C.

[0274] Trans isomer: yellow solid m.p.: 185° C.

[0275] Intermediates 75 and 76

[0276] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(7-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl))-9H-pyrido[3,4-b]indole-3carboxylate,cis isomer and (1S, 3R)-Methyl1,2,3,4-tetrahydro-1-(7-(4-methyl-3,4-dihydro-2H-benzo[1,4oxazinyl))-9H-pyrido[3,4-b]indole-3-carboxylate,Trans Isomer

[0277] The same method, as described for intermediates 54 and 55, butstarting from D-tryptophan methyl ester and4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxaldehyde gaveIntermediate 75 the cis isomer as an oily compound ¹H NMR (CDCl₃) δ(ppm): 7.6-7.1 (m, 5H); 6.9-6.6 (m, 3H); 5.15 (br s, 1H); 4.3 (t, 2H); 4(dd, 1H); 3.8 (s, 3H); 3.3 (t, 2H); 3.3-2.95 (m, 2H); 2.9 (s, 3H); 1.6(br s) and intermediate 76, the trans isomer as white crystals m.p.:119-121° C.

[0278] Intermediate 77

[0279] Methyl1,2,3,4-tetrahydro-1-(5-(N-benzylindolinyl))-9H-pyrido[3,4-b]indole-3-carboxylate,Mixture of (1R, 3R) and (1S, 3R) Isomers

[0280] The same method, as described for intermediates 54 and 55, butstarting from D-tryptophan methyl ester andN-benzylindoline-5-carboxaldehyde gave intermediate 77 as an oilycompound.

[0281] Intermediates 78 and 79

[0282] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-4-carbomethoxyphenyl-9H-pyrido[3,4-b]indole-3-carboxylate,Cis Isomer and (1S, 3R)-methyl1,2,3,4-tetrahydro-1-(4-carbomethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate,Trans Isomer

[0283] The same method, as described for intermediates 54 and 55, butstarting from D-tryptophan methyl ester and methyl 4-formylbenzoate gaveIntermediate 78, the cis isomer as white crystals m.p.: 157-160° C. andIntermediate 79, the trans isomer as pale yellow crystals m.p. 124-126°C.

[0284] Intermediate 80

[0285] (1R, 3R)-Methyl1,2,3,4-tetrahydro-2-2-(benzyloxycarbonyl)-R-prolyl]-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0286] A solution of N-(benzyloxycarbonyl)-D-proline acid chloride (0.64g, 2.4 mmol) in anhydrous dichloromethane (10 mL) was added dropwise toa stirred solution of intermediate 54 (0.7 g, 2 mmol) and triethylamine(0.33 mL, 2.4 mmol) in dichloromethane (15 mL) at −10° C. The mixturewas stirred for 2 h at −10° C. after which it was diluted withdichloromethane (50 mL), washed with hydrochloric acid (1 N), water, asaturated solution of NaHCO₃, a saturated NaCl solution and dried overNa₂SO₄. Evaporation of the solvent and recrystallisation of the crudeproduct from methanol gave the title compound as pale yellow crystals(0.75 g) m.p.: 268-270° C.

[0287] Intermediate 81

[0288] (1R, 3R)-Methyl1,2,3,4-tetrahydro-2-[2-(benzyloxycarbonyl)-S-prolyl]-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0289] A solution of N-(benzyloxycarbonyl)-L-proline acid chloride (0.86g, 3.2 mmol) in anhydrous dichloromethane (10 mL) was added dropwise toa stirred solution of intermediate 54 (0.91 g, 2.6 mmol) andtriethylamine (0.44 mL, 3.2 mmol) in dichloromethane (20 mL) at −10° C.The mixture was stirred for 2 hours at −10° C. after which it wasdiluted with dichloromethane (60 mL), washed with hydrochloric acid(1N), water , a saturated solution of NaHCO₃, a saturated NaCl solutionand dried over Na₂SO₄. Evaporation of the solvent and recrystallisationof the crude product from methanol/water gave the title compound as paleyellow crystals (0.8 g) m.p.: 115-120° C.

[0290] Intermediate 82

[0291] (1R, 3R)-Methyl1,2,3,4-tetrahydro-2-(2-chloropropionyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0292] To a solution of (S)-(-)-2-chloropropionic acid (87 μl, 1 mmol)in anhydrous dichloromethane (15 mL), was added dicyclohexylcarbodiimide(0.23 g, 1.1 mmol). Intermediate 54 (0,35 g, 1 mmol) was then added andthe mixture was stirred at room temperature for 20 hours. The formedprecipitate of dicyciohexylurea was removed by filtration, the filtratewas evaporated in vacuo and the crude product was purified by flashchromatography eluting with toluene/ethyl acetate: 95/5. The oilycompound obtained was then crystallised from ether/hexane to give thetitle compound as pale yellow crystals (0.31 g) m.p.: 125-127° C.

[0293] Intermediate 83

[0294] (1R, 3R)Methyl1,2,3,4-tetrahydro-2-(2-chloropropionyl)-1-3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate

[0295] To a solution of (R)-(+)-2-chloropropionic acid (191 μl, 2.2mmol) in anhydrous dichloromethane (30 mL), was addeddicyclohexylcarbodiimide (0.45 g, 2.2. mol). Intermediate 54 (0,7 g, 2mmol) was then added and the mixture was stirred at room temperature for20 hours. The formed precipitate of dicyclohexylurea was removed byfiltration, the filtrate was evaporated in vacuo and the crude productwas purified by flash chromatography eluting with toluenelethyl acetate:95/5. The oily compound obtained was then cystallised from ether/hexaneto give the title compound as pale yellow crystals (0.74 g) m.p.126-128° C.

[0296] Intermediates 84 and 85

[0297] (1R, 3R)-Methyl1,2,3,4-tetrahydro-1-(3,4-dibenzyloxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylatecis isomer and (1S, 3R)-methyl1,2,3,4-tetrahydro-1-(3,4-dibenzyloxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate Trans Isomer

[0298] The same method as described for intermediates 54 and 55 butstarting from D-tryptophan methyl ester and 3,4dibenzyloxybenzaldehydegave intermediate 84, the cis isomer as an oily compound 1H NMR (CDCl₃)δ(ppm): 7.5-6.95 (m, 15H); 6.85 (s, 1H); 6.75 (s, 2H); 5.1 (s, 2H); 5(br s, 1H); 4.95 (d, 2H) 3.85 (dd, 1H); 3.7 (s, 3H); 3.2-2.8 (m, 2H);2.3 (br s, 1H) and intermediate 85, the trans isomer as an oily compound¹HNMR (CDCl₃) δ (ppm) 7.6-7 (m, 15H); 6.9-6.7 (m, 3H); 5.2 (br s, 1H);5.1 (s, 2H); 5 (s, 2H); 3.8 (t, 1H); 3.65 (s, 3H); 3.3-3 (m, 2H); 2.25(br s, 1H).

[0299] Intermediate 86

[0300] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-dibenzyloxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0301] The same two step procedure but starting from intermediate 84 andmethylamine gave, after recrystallisation from dichloromethane/ether,the title compound as white crystals m.p.: 158-160° C., [α]^(20°)_(D)=+11.7° (c=1.23; CHCl₃).

[0302] Intermediate 87

[0303] Methyl1,2,3,4-tetrahydro-1-(5-(2-methylisoindolinyl))-9H-pyrido[3,4-b]indole-3-carboxylate,Mixture of (1R, 3R) and (1S,3R) Isomers

[0304] The same method, as described for intermediates 54 and 55, butstarting from D-tryptophan methyl ester andN-methylisoindoline-5carboxaldehyde gave intermediate 87 as an oilycompound.

EXAMPLE 1

[0305]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyohenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0306] a) To a stirred solution of intermediate 1 (2 g) and NaHCO₃ (0.6g) in anhydrous CHCl₃ (40 mL) was added dropwise chloroacetyl chloride(1.1 mL) at 0° C. The resulting mixture was stirred for 1 hour at thesame temperature and diluted with CHCl₃. Water (20 mL) was then addeddropwise with stirring to the mixture, followed by a saturated solutionof NaHCO₃. The organic layer was washed with water until neutrality anddried over Na₂SO₄. After evaporation of the solvent under reducedpressure, cis-methyl1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylatewas Obtained as an Oil which was Crystallised from Ether (2 g, m.p.:215-218° C.) and was used without further purification in the next step.

[0307] b) To a stirred suspension of the chloroacetyl intermediate (0.34g) in MeOH (20 mL) was added at ambient temperature a solution ofmethylamine (33% in EtOH) (0.37 mL) and the resulting mixture was heatedat 50° C. under N₂ for 14 hours. The solvent was removed under reducedpressure and the residue was dissolved in CH₂Cl₂ (50 mL). After washingwith water (3×30 mL), drying over Na₂SO₄ and evaporating to dryness, theresidue was purified by flash chromatography eluting with CH₂Cl₂/MeOH(99/1) and recrystallised from MeOH to give the title compound as whitecrystals (0.19 g) m.p. 253-255° C.

[0308] Analysis for C₂₂H₁₉N₃O_(4:)

[0309] Calculated: C, 67.86; H, 4.92; N, 10.79;

[0310] Found: C, 67.53; H, 4.99; N, 10.62%.

[0311] The following compounds were obtained in a similar manner:

EXAMPLE 2

[0312] Cis-2, 3, 6, 7, 12,12a-hexahydro-2-butyl-10-fluoro-6-4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole1,4-dione

[0313] The same two step procedure but starting from butylamine andintermediate 52 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: 182° C.

[0314] Analysis for C₂₅H₂₆FN₃O₃ (0.1 H₂O):

[0315] Calculated: C, 68.67 ; H, 6.04 ; N, 9.61;

[0316] Found: C, 68.38; H, 6.11; N, 9.53%.

EXAMPLE 3

[0317]Trans-2,3,6,7,12,12a-hexahydro-2-methyl(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0318] The same two step procedure but starting from methylamine andintermediate 2 gave, after recrystallisation from toluene, the titlecompound as white crystals m.p.: 301-303° C.

[0319] Analysis for C₂₂H₁₉N₃O₄:

[0320] Calculated: C, 67.86; H, 4.92; N, 10.79;

[0321] Found: C, 67.98; H, 4.98; N, 10.73%.

EXAMPLE 4

[0322]Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxyohenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0323] The same two step procedure but starting from ammonia andintermediate 1 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 283-285° C.

[0324] Analysis for C₂₁H₁₇N₃O₄:

[0325] Calculated: C, 67.19; H, 4.56; N, 11.19;

[0326] Found: C, 67.04; H, 4.49; N, 11.10%.

EXAMPLE 5

[0327]Cis-2,3,6,7,12,12a-hexahydro-10-fluoro-6-(4-methoxyphenyl)-2-2,2,2-trifluoroethyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0328] The same two step procedure but starting from2,2,2-trifluoroethylamine and intermediate 52 gave, afterrecrystallisation from ethanolidiisopropyl ether, the title compound aswhite crystals m.p.: 190° C.

[0329] Analysis for C₂₃H₁₉F₄N₃O₃:

[0330] Calculated: C, 59.87; H, 4.15; N, 9.11;

[0331] Found: C, 59.81; H, 4.18; N, 9.21%.

EXAMPLE 6

[0332]Cis-2,3,6,7,12,12a-hexahydro-10-fluoro-2--methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0333] The same two step procedure but starting from methylamine andintermediate 50 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: 292° C.

[0334] Analysis for C₂₂H₁₈FN₃O₄:

[0335] Calculated: C, 64.86; H, 4.45; N, 10.31;

[0336] Found: C, 64.66; H, 4.60; N, 10.21%.

EXAMPLE 7

[0337] (6R12aS)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0338] The same two step procedure but starting from methylamine and thetrans isomer of intermediate 56 gave, after recrystallisation fromtoluene, the title compound as white crystals m.p.: 287-289° C.

[0339] Analysis for C₂₂H₁₉N₃O₄ (0.25 toluene):

[0340] Calculated: C, 69.16; H, 5.13; N, 10.19;

[0341] Found: C, 69.09; H, 5.14; N, 10.19%.

[0342] [α]_(D) ^(20°)=−293.4° (C=1.28; CHCl₃).

EXAMPLE 8

[0343] (6S,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0344] The same two step procedure but starting from methylamine andintermediate 55 gave, after recrystallisation from toluene, the titlecompound as white crystals m.p.: 287° C.

[0345] Analysis for C₂₂H₁₉N₃O₄ (0.3 toluene):

[0346] Calculated: C, 69.41; H, 5.17; N, 10.08;

[0347] Found: C, 69.56: H, 5.24; N, 10.08%.

[0348] [α]_(D) ^(20°)=+297.9° (C=1.21; CHCl₃).

EXAMPLE 9

[0349] Cis-2,3,6,7,12,12a-hexahydro-2-[2-(2-pyridyl)-ethyl]-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′-6,1]pyrido[3,4-b]indole-1,4-dione

[0350] The same two step procedure but starting from2-2-pyridyl)ethylamine and intermediate 1 gave, after recrystallisationfrom 2-propanol, the title compound as white crystals m.p.: 218-222° C.

[0351] Analysis for C₂₈H₂₄N₄O₄:

[0352] Calculated: C, 69.99; H, 5.03; N, 11.66;

[0353] Found: C, 69.92; H, 5.16; N, 11.48%.

EXAMPLE 10

[0354]Cis-2,3,6,7,12,12a-hexahydro-2-(2-pyridylmethyl)-6-(3,4-methylenedioxyphenyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0355] The same two step procedure but starting from2-pyridylmethylamine and intermediate 1 gave, after recrystallisationfrom DMF/water, the title compound as cream crystals m.p: 285-286° C.

[0356] Analysis for C₂₇H₂₂N₄O₄ (0.4 H₂O):

[0357] Calculated: C, 68.46; H, 4.85; N, 11.83;

[0358] Found: C, 68.58; H, 4.88; N, 11.90%.

EXAMPLE 11

[0359]Cis-2,3,6,7,12,12a-hexahydro-2-(3-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0360] The same two step procedure but starting from3-pyridylmethylamine and intermediate 1 gave, after recrystallisationfrom CH₂Cl₂/MeOH, the title compound as cream crystals m.p.: 292-293° C.

[0361] Analysis: C₂₇H₂₂N₄O₄:

[0362] Calculated: C, 69.52; H, 4.75; N, 12.01;

[0363] Found: C, 69.27; H, 4.74; N, 11.37%.

EXAMPLE 12

[0364]Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0365] The same two step procedure but starting from4-pyridylmethylamine and intermediate 1 gave, after recrystallisationfrom MeOH, the title compound as pale yellow crystals m.p.: 273-274° C.

[0366] Analysis for C₂₇H₂₂N₄O₄ (1.8 H₂O):

[0367] Calculated: C, 65.00; H, 5.17; N, 11.23;

[0368] Found: C, 65.11; H, 4.85; N, 11.07%.

EXAMPLE 13

[0369]Cis-2,3,6,7,12,12a-hexahydro-2-ethyl-6-(3,4methylenedioxyrhenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0370] The same two step procedure but starting from ethylamine andintermediate 1 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 272-274° C.

[0371] Analysis for C₂₃H₂₁N₃O₄:

[0372] Calculated: C, 68.47; H, 5.25; N, 10.42;

[0373] Found: C, 68.52; H, 5.35; N, 10.53%.

EXAMPLE 14

[0374]Cis-2,3,6,7,12,12a-hexahydro-2-(2,2,2-trifluoroethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0375] The same two step procedure but starting from2,2,2-trifluoroethylamine and intermediate 1 gave, afterrecrystallisation from EtOH, the title compound as white crystals m.p.:303° C.

[0376] Analysis for C₂₃H₁₈F₃N₃O₄:

[0377] Calculated: C, 60.40; H, 3.97; N, 9.19;

[0378] Found: C, 60.43; H, 4.15; N, 9.16%.

EXAMPLE 15

[0379]Cis-2,3,6,7,12,12a-hexahydro-6-3,4-methylenedioxyphenyl)-2-propyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0380] The same two step procedure but starting from propylamine andintermediate 1 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 270-271° C.

[0381] Analysis for C₂₄H₂₃N₃O₄:

[0382] Calculated: C, 69.05; H, 5.55; N, 10.07;

[0383] Found: C, 69.22; H, 5.50; N, 9.80%.

EXAMPLE 16

[0384]Cis-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1.4-dione

[0385] The same two step procedure but starting from isopropylamine andintermediate 1 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 248-250° C.

[0386] Analysis for C₂₄H₂₃N₃O₄:

[0387] Calculated: C, 69.05; H, 5.55; N, 10.07;

[0388] Found: C, 68.86; H, 5.66; N, 0.21%.

EXAMPLE 17

[0389]Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0390] The same two step procedure but starting from cyclopropylamineand intermediate 1 gave, after recrystallisation from methanol, thetitle compound as white crystals m.p. 290-292° C.

[0391] Analysis for C₂₄H₂₁N₃O₄:

[0392] Calculated: C, 69.39; H, 5.10; N, 10.11;

[0393] Found: C, 69.11 ; H, 5.20; N, 9.94%.

EXAMPLE 18

[0394]Cis-2,3,6,7,12,12a-hexahydro-2-butyl(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0395] The same two step procedure but starting from butylamine andintermediate 1 gave, after recrystallisation from methanol/water, thetitle compound as white crystals m.p.: 241-243° C.

[0396] Analysis for C₂₅H₂₅N₃O₄:

[0397] Calculated: C, 69.59; H, 5.84; N, 9.74;

[0398] Found: C, 69.77; H, 5.82; N, 9.81%.

EXAMPLE 19

[0399]Trans-2,3,6,7,12,12a-hexahydro-2-butyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0400] The same two step procedure but starting from butylamine andintermediate 2 gave, after recrystallisation from toluene, the titlecompound as white crystals m.p.: 243° C.

[0401] Analysis for C₂₅H₂₅N₃O₄:

[0402] Calculated: C, 69.59; H, 5.84; N, 9.74;

[0403] Found: C, 69.80; H, 5.78; N, 9.52%.

EXAMPLE 20

[0404]Cis-2,3,6,7,12,12a-hexaydro-2-cyclopropylmethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0405] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 1 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 217-218° C.

[0406] Analysis for C₂₅H₂₃N₃O₄:

[0407] Calculated: C, 69.92; H, 5.40; N, 9.78;

[0408] Found: C, 70.02; H, 5.47; N, 9.84%.

EXAMPLE 21

[0409]Cis-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0410] The same two step procedure but starting from cyclopentylamineand intermediate 1 gave, after recrystallisation from acetone, the titlecompound as white crystals m.p.: 270° C.

[0411] Analysis for C₂₆H₂₅N₃O₄:

[0412] Calculated: C, 70.41; H, 5.68; N, 9.47;

[0413] Found: C, 70.58; H, 5.63; N, 9.38%.

EXAMPLE 22

[0414]Cis-2,3,6,7,12,12a-hexahydro-2-cyclohexyl-6-3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0415] The same two step procedure but starting from cyclohexylamine andintermediate 1 gave, after recrystallisation from methanol/water, thetitle compound as white crystals m.p.: 268-269° C.

[0416] Analysis for C₂₇H₂₇N₃O₄:

[0417] Calculated: C, 70.88; H, 5.95; N, 9.18;

[0418] Found: C, 70.82; H, 5.89; N, 9.21%.

EXAMPLE 23

[0419]Cis-2,3,6,7,12,12a-hexahydro-2-benzyl-6-3,4-methylenedioxyohenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0420] The same two step procedure but starting from benzylamine andintermediate 1 gave, after recrystallisation fromdichloromethane/hexane, the title compound as white crystals m.p.285-287° C.

[0421] Analysis for C₂₈H₂₃N₃O₄(1 H₂O):

[0422] Calculated: C, 69.55; H, 5.21; N, 8.69;

[0423] Found: C, 69.30; H, 5.06; N, 8.48%.

EXAMPLE 24

[0424]Cis-2,3,6,7,12,12a-hexahydro-2-(4-fluorobenzyl)-6-(3,4-ethylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0425] The same two step procedure but starting from 4fluorobenzylamineand intermediate 1 gave, after recrystallisation from acetone, the titlecompound as white crystals m.p.: 281-283° C.

[0426] Analysis for C₂₈H₂₂FN₃O₄:

[0427] Calculated: C, 69.56; H, 4.59; F, 3.93; N, 8.69;

[0428] Found: C69.54; H, 4.58; F, 3.82; N, 8.63%.

EXAMPLE 25

[0429]Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-ione

[0430] The same two step procedure but starting from methylamine andintermediate 3 gave, after recrystallisation from 2propanol, the titlecompound as white crystals m.p.: 257-263° C.

[0431] Analysis for C₂₂H₂₁N₃O₃:

[0432] Calculated: C, 70.38; H, 5.64; N, 11.19;

[0433] Found: C, 70.11; H, 5.55; N, 11.15%.

EXAMPLE 26

[0434]Trans-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0435] The same two step procedure but starting from methylamine andintermediate 4 gave, after recrystallisation from diisopropyl ether, thetitle compound as white crystals m.p.: 225-228° C.

[0436] Analysis for C₂₂H₂₁ N₃O₃:

[0437] Calculated: C, 70.38; H, 5.64; N, 11.19;

[0438] Found: C, 70.34; H, 5.77; N, 11.19%.

EXAMPLE 27

[0439]Cis-2,3,6,7,12,12a-hexahydro-2-ethyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0440] The same two step procedure but starting from ethylamine andintermediate 3 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 245-255° C.

[0441] Analysis for C₂₃H₂₃N₃O₃:

[0442] Calculated: C, 70.93; H, 5.95; N, 10.79;

[0443] Found: C, 70.74; H, 6.06; N, 10.87%.

EXAMPLE 28

[0444]Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-2,2,2-trifluoroethyl)pyrazino[2′1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0445] The same two step procedure but starting from2,2,2-trifluoroethylamine and intermediate 3 gave, afterrecrystallisation from ethanol , the title compound as white crystalsm.p.: 232° C.

[0446] Analysis for C₂₃H₂₀F₃N₃O₃:

[0447] Calculated: C, 62.30; H, 4.55; N, 9.48;

[0448] Found: C, 62.08; H, 4.66; N, 9.54%.

EXAMPLE 29

[0449]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methoxyphenyl)-Pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0450] The same two step procedure but starting from butylamine andintermediate 3 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 157° C.

[0451] Analysis for C₂₅H₂₇N₃O₃(0.5H₂O):

[0452] Calculated: C, 70.40; H, 6.62; N, 9.85;

[0453] Found: C, 70.25; H, 6.60; N, 9.83%.

EXAMPLE 30

[0454]Trans-2,3,6,7,12,12a-hexahydro-2-butyl-6-4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0455] The same two step procedure but starting from butylamine andintermediate 4 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 212-214° C.

[0456] Analysis for C₂₅H₂₇N₃O₃:

[0457] Calculated: C, 71.92; H, 6.52; N, 10.06;

[0458] Found: C, 71.81; H, 6.55; N, 10.03%.

EXAMPLE 31

[0459]Cis-2,3,6,7,12,12a-hexahydro-6-(4-methoxyphenyl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0460] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 3 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 180-185° C.

[0461] Analysis for C₂₅H₂₅N₃O₃ (0.5H₂O):

[0462] Calculated: C, 70.74; H, 6.17; N, 9.90;

[0463] Found: C, 70.91; H, 6.16; N, 9.80%.

EXAMPLE 32

[0464]Cis-2,3,6,7,12,12a-hexahydro-2-benzyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0465] The same two step procedure but starting from benzylamine andintermediate 3 gave, after recrystallisation from acetone, the titlecompound as white crystals m.p.: 275-279° C.

[0466] Analysis for C₂₈H₂₅N₃O₃:

[0467] Calculated: C, 74.48; H, 5.58; N, 9.31;

[0468] Found: C, 74.53; H, 5.60; N, 9.20%.

EXAMPLE 33

[0469]Cis-2,3,6,7,12,12a-hexahydro-6-(3-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0470] The same two step procedure but starting from methylamine andintermediate 5 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 267-269° C.

[0471] Analysis for C₂₂H₂₁N₃O₃:

[0472] Calculated: C, 70.38; H, 5.64; N, 11.19;

[0473] Found: C, 70.32; H, 5.59; N, 11.25%.

EXAMPLE 34

[0474]Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole -1,4-dione

[0475] The same two step procedure but starting from methylamine andintermediate 6 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 247-248° C.

[0476] Analysis for C₂₃H₂₃N₃O₃:

[0477] Calculated: C, 70.93. H, 5.95; N, 10.79;

[0478] Found: C, 71.23; H, 5.95; N, 10.63%.

EXAMPLE 35

[0479]Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethoxyphenyl)-2cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0480] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 6 gave, after recrystallisationfrom 2-propanol, the title compound as white crystals m.p.: 160-162° C.

[0481] Analysis for C₂₆H₂₇N₃O₃:

[0482] Calculated: C, 72.71; H, 6.34; N, 9.78;

[0483] Found: C, 72.28; H, 6.39; N, 9.71%.

EXAMPLE 36

[0484]Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0485] The same two step procedure but starting from methylamine andintermediate 8 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 292-294° C.

[0486] Analysis for C₂₃H₂₁N₃O₃:

[0487] Calculated: C, 71.30; H, 5.46; N, 10.85;

[0488] Found: C, 71.15; H, 5.56; N, 10.84%.

EXAMPLE 37

[0489]Cis-2,3,6,7,12,12a-hexahydro-6-2,3-dihydrobenzo[b]furan-5-yl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0490] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 8 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 165-166° C.

[0491] Analysis for C₂₆H₂₅N₃O₃:

[0492] Calculated: C, 73.05; H, 5.89; N, 9.83;

[0493] Found: C, 73.08; H, 5.97; N, 9.87%.

EXAMPLE 38

[0494]Cis-2,3,6,7,12,12a-hexahydro(3,4ethylenedioxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0495] The same two step procedure but starting from methylamine andintermediate 10 gave, after recrystallisation from acetone, the titlecompound as white crystals m.p.: 303-305° C.

[0496] Analysis for C₂₃H₂₁N₃O₄:

[0497] Calculated: C, 68.47; H, 5.25; N, 10.42;

[0498] Found: C, 68.35; H, 5.31 ; N, 10.27%.

EXAMPLE 39

[0499]Cis-2,3,6,7,12,12a-hexahydro(3,4-ethylenedioxyphenyl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0500] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 10 gave, after recrystallisationfrom dichloromethane/ether, the title compound as white crystals m.p.:288-290° C.

[0501] Analysis for C₂₆H₂₅N₃O₄:

[0502] Calculated: C, 70.41; H, 5.68; N, 9.47;

[0503] Found: C, 70.15; H, 5.62; N, 9.30%.

EXAMPLE 40

[0504]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(2-chlorophenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0505] The same two step procedure but starting from butylamine andintermediate 12 gave, after recrystallisation from methanol/water, thetitle compound as white crystals m.p.: 146° C.

[0506] Analysis for C₂₄H₂₄ClN₃O₂(0.75 H₂O):

[0507] Calculated: C, 66.20; H, 5.90; N, 9.65;

[0508] Found: C, 66.15; H, 5.95; N, 9.69%.

EXAMPLE 41

[0509]Cis-2,3,6,7,12,12a-hexahydro-6-(4-chlorophenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0510] The same two step procedure but starting from methylamine andintermediate 13 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 274° C.

[0511] Analysis for C₂₁H₁₈ClN₃O₂ (0.25 H₂O):

[0512] Calculated: C, 65.63; H, 4.85; N, 10.93;

[0513] Found: C, 65.39; H, 4.84; N, 10.85%.

EXAMPLE 42

[0514]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-4-chlorophenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4dione

[0515] The same two step procedure but starting from butylamine andintermediate 13 gave, after recrystallisation from ethanol/water, thetitle compound as white crystals m.p.: 164-166° C.

[0516] Analysis for C₂₄H₂₄ClN₃O₂:

[0517] Calculated: C, 68.32; H, 5.73; Cl, 8.40; N, 9.96;

[0518] Found: C, 68.48; H, 5.64; Cl, 8.37; N, 9.99%.

EXAMPLE 43

[0519]Cis-2,3,6,7,12,12a-hexahydro-6-(3,4-dichlorophenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0520] The same two step procedure but starting from methylamine andintermediate 15 gave, after recrystallisation from ethanol/DMF, thetitle compound as white crystals m.p.: >260° C.

[0521] Analysis for C₂₁H₁₇Cl₂N₃O₂ (0.5 H₂O):

[0522] Calculated: C, 59.39; H, 4.29; N, 9.93;

[0523] Found: C, 59.32; H, 4.16; N, 9.99%.

EXAMPLE 44

[0524]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-phenyl-pyrazino[2′1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0525] The same two step procedure but starting from butylamine andcis-methyl1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate¹ gave,after recrystallisation from methanol/water, the title compound as whitecrystals m.p.: 243-245° C.

[0526] Analysis for C₂₄H₂₅N₃O₂:

[0527] Calculated: C, 74.39; H, 6.50; N, 10.84;

[0528] Found: C, 74.54; H, 6.51; N, 10.86%.

[0529] 1. D. Soerens et al., J. Org. Chem. 44, 535-545 (1979).

EXAMPLE 45

[0530]Cis-2,3,6,7,12,12a-hexahydro-2-benzyl-6-phenyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0531] The same two step procedure but starting from benzylamine andcis-methyl-1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylategave, after recrystallisation from methanol, the title compound as whitecrystals m.p. 193-195° C.

[0532] Analysis for C₂₇H₂₃N₃O₂:

[0533] Calculated: C, 76.94; H, 5.50; N, 9.97;

[0534] Found: C, 77.23; H, 5.54; N, 9.97%.

EXAMPLE 46

[0535]Trans-2,3,6,7,12,12a-hexahydro-2-benzyl-6-phenyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0536] The same two step procedure but starting from benzylamine andcis-methyl-1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylategave, after recrystallisation from methanol, the title compound as whitecrystals m.p.: 284° C.

[0537] Analysis for C₂₇H₂₃N₃O₂:

[0538] Calculated: C, 76.94; H, 5.50; N, 9.97;

[0539] Found: C, 76.88; H, 5.45; N, 9.89%.

EXAMPLE 47

[0540]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(1,2,3,4-tetrahydro-6-naphthyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0541] The same two step procedure but starting from methylamine andintermediate 17 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: >260° C.

[0542] Analysis for C₂₅H₂₅N₃O₂:

[0543] Calculated: C, 75.16; H, 6.31; N, 10.52;

[0544] Found: C, 74.93; H, 6.43; N, 10.63%.

EXAMPLE 48

[0545]Cis-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(1,2,3,4-tetrahydro-6-naphthyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0546] The same two step procedure but starting from isopropylamine andintermediate 17 gave, after recrystallisation from the title compound asoff-white crystals m.p.: 244-246° C.

[0547] Analysis for C₂₇H₂₉N₃O₂ (0.25H₂O):

[0548] Calculated: C, 75.06; H, 6.88; N, 9.73;

[0549] Found: C, 75.00; H, 6.83; N, 9.69%.

EXAMPLE 49

[0550]Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(1,2,3,4-tetrahydro-6-naphthyl))-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0551] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 17 gave, after recrystallisationfrom ethanol/pentane, the title compound as white crystals m.p.: 125° C.

[0552] Analysis for C₂₈H₂₉N₃O₂ (0.25 H₂O);

[0553] Calculated: C, 75.73; H, 6.70; N, 9.46;

[0554] Found: C, 75.45; H, 6.86; N, 9.14%.

EXAMPLE 50

[0555]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(2-naphthyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0556] The same two step procedure but starting from methylamine andintermediate 18 gave, after recrystallisation fromdichloromethane/methanol, the title compound as white crystalsm.p.: >260° C.

[0557] Analysis for C₂₅H₂₁N₃O₂ (0.25H₂O):

[0558] Calculated: C, 75.08; H, 5.42; N, 10.51;

[0559] Found: C, 75.35; H, 5.42; N, 10.49%.

EXAMPLE 51

[0560]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(2-thienyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0561] The same two step procedure but starting from butylamine andintermediate 20 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: 226° C.

[0562] Analysis for C₂₂H₂₃N₃O₂S:

[0563] Calculated: C, 67.15; H, 5.89; N, 10.68;

[0564] Found: C, 67.39; H, 5.88; N, 10.77%.

EXAMPLE 52

[0565]Cis-2,3,6,7,12,12a-hexahydro-6-bromo-2-thienyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0566] The same two step procedure but starting from methylamine andintermediate 24 gave, after recrystallisation from ethanol, the titlecompound as a cream powder m.p.: 258° C.

[0567] Analysis for C₁₉H₁₆BrN₃O₂S:

[0568] Calculated: C, 53.03; H, 3.75; N, 9.76;

[0569] Found: C, 53.01 ; H, 3.78; N, 9.69%.

EXAMPLE 53

[0570]Cis-2,3,6,7,12,12a-hexahydro-6-(4-bromo-2-thienyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0571] The same two step procedure but starting from methylamine andintermediate 26 gave, after recrystallisation from ethanol, the titlecompound as white crystals mp.: 292° C.

[0572] Analysis for C₁₉H₁₆BrN₃O₂S (0.25H₂O):

[0573] Calculated: C, 52.48; H, 3.82; N, 9.66;

[0574] Found: C, 52.46; H, 3.81 ; N, 9.60%.

EXAMPLE 54

[0575]Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0576] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 24 gave, after recrystallisationfrom ethanol, the title compound as white crystals m.p.: 190° C.

[0577] Analysis for C₂₂H₂₀BrN₃O₂S:

[0578] Calculated: C, 56.18; H, 4.29; N, 8.93;

[0579] Found: C, 55.92; H, 4.28; N, 8.74%.

EXAMPLE 55

[0580]Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-cylopentyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0581] The same two step procedure but starting from cyclopentylamineand intermediate 24 gave, after recrystallisation from ethanol, thetitle compound as white crystals m.p.: 252° C.

[0582] Analysis for C₂₃H₂₂BrN₃O₂S:

[0583] Calculated: C, 57.03; H, 4.58; N, 8.67;

[0584] Found: C, 56.87; H, 4.66; N, 8.68%.

EXAMPLE 56

[0585]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(5-methyl-2-thienyl)-pyrazino[2′,140 :6,1]pyrido[3,4-b]indole-1,4-dione

[0586] The same two step procedure but starting from methylamine and thecis isomer of intermediate 66 gave, after recrystallisation fromethanol, the title compound as white crystals m.p.: 282° C.

[0587] Analysis for C₂₀H₁₉N₃O₂S (0.25H₂O):

[0588] Calculated: C, 64.93; H, 5.31; N, 11.36;

[0589] Found: C, 64.84; H, 5.28; N, 10.81%.

EXAMPLE 57

[0590]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-thienyl)-pyrazino[2′,140:6,1]pyrido[3,4b]indole -1,4-dione

[0591] The same two step procedure but starting from methylamine andintermediate 22 gave, after recrystallisation from acetone, the titlecompound as white crystals m.p.: 290-295° C.

[0592] Analysis for C₁₉H₁₇N₃O₂S:

[0593] Calculated: C, 64.94; H, 4.88; N, 11.96;

[0594] Found: C, 64.81; H, 4.95; N, 11.68%.

EXAMPLE 58

[0595]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(3-thienyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4dione

[0596] The same two step procedure but starting from butylamine andintermediate 22 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 236-239° C.

[0597] Analysis for C₂₂H₂₃N₃O₂S:

[0598] Calculated: C, 67.15; H, 5.89; N, 10.68; S,8.15;

[0599] Found: C, 67.42; H, 5.76; N, 10.57; S,8.01%.

EXAMPLE 59

[0600]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-furyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0601] The same two step procedure but starting from methylamine and thecis isomer of intermediate 28 gave, after recrystallisation from ether,the title compound as a white solid m.p.: 250° C.

[0602] Analysis for C₁₉H₁₇N₃O₃ (0.5H₂O):

[0603] Calculated: C, 66.27; H, 5.27; N, 12.20;

[0604] Found: C, 66.33; H, 5.48; N, 12.02%.

EXAMPLE 60

[0605]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(5-methyl-2-furyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4dione

[0606] The same two step procedure but starting from methylamine andintermediate 29 gave, after recrystallisation from ethanol, the titlecompound as a cream powder m.p.: 303° C.

[0607] Analysis for C₂₀H₁₉N₃O₃ (0.25H₂O):

[0608] Calculated: C, 67.88; H, 5.55; N, 11.87;

[0609] Found: C, 67.90; H, 5.50; N, 11.98%.

EXAMPLE 61

[0610]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0611] The same two step procedure but starting from methylamine andintermediate 31 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.:>260° C.

[0612] Analysis for C₂₂H₂₁N₃O₂ (0.25 H₂O):

[0613] Calculated: C, 72.61 ; H, 5.95; N, 11.55;

[0614] Found: C, 72.73; H, 5.96; N, 11.59%.

EXAMPLE 62

[0615]Cis-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(4-methylphenyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0616] The same two step procedure but starting from isopropylamine andintermediate 31 gave, after recrystallisation from the title compound aswhite crystals m.p.: 170° C.

[0617] Analysis for C₂₄H₂₅N₃O₂ (0.5H₂O):

[0618] Calculated: C, 72.70; H, 6.61; N, 10.60;

[0619] Found: C, 73.06; H, 6.43; N, 9.66%.

EXAMPLE 63

[0620]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0621] The same two step procedure but starting from butylamine andintermediate 31 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 194° C.

[0622] Analysis for C₂₅H₂₇N₃O₂ (0.5H₂O):

[0623] Calculated: C, 73.15; H, 6.87; N, 10.24;

[0624] Found: C, 73.01 ; H, 6.84.N, 10.26%.

EXAMPLE 64

[0625]Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0626] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 31 gave, after recrystallisationfrom methano/water, the title compound as white crystals m.p.: 194° C.

[0627] Analysis for C₂₅H₂₅N₃O₂ (1.1H₂O):

[0628] Calculated: C, 71.61; H, 6.54; N, 10.02;

[0629] Found: C, 71.42.H, 6.07; N, 9.95%.

EXAMPLE 65

[0630]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b[indole-1,4-dione

[0631] The same two step procedure but starting from methylamine andintermediate 33 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: >260° C.

[0632] Analysis for C₂₂H21N₃O₂:

[0633] Calculated: C, 73.52; H, 5.89; N, 11.69;

[0634] Found: C, 73.60; H, 5.97; N, 11.66%.

EXAMPLE 66

[0635]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-trifluoromethylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0636] The same two step procedure but starting from butylamine andintermediate 35 gave, after recrystallisation from methanol/water, thetitle compound as white crystals m.p.: 155° C.

[0637] Analysis for C₂₅H₂₄F₃N₃O₂ (0.5H₂O):

[0638] Calculated: C, 64.65; H, 5.43; N, 9.05;

[0639] Found: C, 64.78; H, 5.40; N, 9.01%.

EXAMPLE 67

[0640]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-trifluoromethoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0641] The same two step procedure but starting from methylamine and thecis isomer of intermediate 65 gave, after recrystallisation frommethanol, the title compound as white crystals m.p.: 174-180° C.

[0642] Analysis for C₂₂H₁₈F₃N₃O₃ (0.5H₂O):

[0643] Calculated: C, 60.27; H, 4.37; N, 9.58;

[0644] Found: C, 60.24; H, 4.28; N, 19.50%.

EXAMPLE 68

[0645]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(4-hydroxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0646] The same two step procedure but starting from methylamine andintermediate 33 gave, after recrystallisation from methanol, the titlecompound as yellow crystals m.p.: 179-180° C.

[0647] Analysis for C₂₁H₁₉N₃O₃(1.25H₂O):

[0648] Calculated: C, 65.70; H, 5.64; N, 10.94;

[0649] Found: C, 65.46; H, 5.45; N, 10.92%.

EXAMPLE 69

[0650]Cis-2,3,6,7,12,12a-hexahydro--6-(3-hydroxy-4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0651] The same two step procedure but starting from methylamine andintermediate 40 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: 320° C.

[0652] Analysis for C₂₂H₂₁N₃O₄(0.25H₂O):

[0653] Calculated: C, 66.74; H, 5.47; N, 10.61;

[0654] Found: C, 66.72; H, 5.46; N, 10.53%.

EXAMPLE 70

[0655]Cis-2,3,6,7,12,12a-hexahydro-6-(4-hydroxy-3-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1.4-dione

[0656] The same two step procedure but starting from methylamine andintermediate 41 gave, after recrystallisation fromdichloromethanelethanol, the title compound as yellow crystals m.p.:264-265° C.

[0657] Analysis for C₂₂H₂₁N₃O₄:

[0658] Calculated: C, 67.51; H, 5.41; N, 10.74;

[0659] Found: C, 67.05; H, 5.41; N, 10.62%.

EXAMPLE 71

[0660]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-cyanophenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0661] The same two step procedure but starting from butylamine andintermediate 37 gave, after recrystallisation from methanol/water, thetitle compound as white crystals m.p.: 246° C.

[0662] Analysis for C₂₅H₂₄N₄O₂ (1H₂O):

[0663] Calculated: C, 69.75; H, 6.09; N, 13.01;

[0664] Found: C, 69.50; H, 5.96; N, 12.86%.

EXAMPLE 72

[0665]Cis-2,3,6,7,12,12a-hexahydro-6--ethylphenyl)-2-isopropyl-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0666] The same two step procedure but starting from isopropylamine andthe cis isomer of intermediate 42 gave, after recrystallisation fromn-pentane, the title compound as white crystals m.p.: 130° C.

[0667] Analysis for C₂₅H₂₇N₃O₂ (0.5H₂O):

[0668] Calculated: C, 73. 15; H, 6.87; N, 10.24;

[0669] Found: C, 73.39; H, 7.08; N, 9.81%.

EXAMPLE 73

[0670] Cis-2,3,6,7,12,12a-hexahydro-6-(4ethylphenyl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0671] The same two step procedure but starting fromcyclopropylmethylamine and the cis isomer of intermediate 42 gave, afterrecrystallisation from ethanol, the title compound as white crystalsm.p.: 160° C.

[0672] Analysis for C₂₆H₂₇N₃O₂:

[0673] Calculated: C, 75.52; H, 6.58; N, 10.16;

[0674] Found: C, 75.54; H, 6.62; N, 10.08%.

EXAMPLE 74

[0675]Cis-2,3,6,7,12,12a-hexahydro-6-(4-isopropylphenyl)-2methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0676] The same two step procedure but starting from methylamine andintermediate 43 gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: 244° C.

[0677] Analysis for C₂₄H₂₅N₃O₂:

[0678] Calculated: C, 74.39; H, 6.50; N, 10.84;

[0679] Found: C, 74.27; H, 6.53; N, 11.05%.

EXAMPLE 75

[0680]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-4nitrophenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0681] The same two step procedure but starting from butylamine andintermediate 45 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 182° C.

[0682] Analysis for C₂₄H₂₄N₄O₄ (0.25H₂O):

[0683] Calculated: C, 65.97; H, 5.65; N, 12.82;

[0684] Found: C, 65.92; H, 5.62; N, 12.96%.

EXAMPLE 76

[0685]Cis-2,3,6,7,12,12a-hexahydro-6-(4dimethylaminophenyl)-2methyl-pyrazino[2′,1′:6,1]pyrido]3,4-b]indole-1,4-dione

[0686] The same two step procedure but starting from methylamine and thecis isomer of intermediate 47 gave after recrystallisation frommethanol, the title compound as white crystals m.p.: 266° C.

[0687] Analysis for C₂₃H₂₄N₄O₂:

[0688] Calculated: C, 71.11; H, 6.23; N, 14.42;

[0689] Found: C, 71.19; H, 6.24; N, 14.34%.

EXAMPLE 77

[0690]Cis-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3-pyridyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0691] The same two step procedure but starting from methylamine andintermediate 48 gave after recrystallisation from chloroform, the titlecompound as white crystals m.p.: 312° C.

[0692] Analysis for C₂₀H₁₈N₄O₂:

[0693] Calculated: C, 69.35; H, 5.24; N, 16.17;

[0694] Found: C, 69.08; H, 5.20; N, 16.19%.

EXAMPLE 78

[0695] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0696] a) To a stirred solution of intermediate 54 (0.5 g) and NaHCO₃(0.14 g) in anhydrous CHCl₃ (20 mL) was added dropwise chloroacetylchloride (0.27 mL) at 0° C. The resulting mixture was stirred for 1 hourat the same temperature and diluted with CHCl₃ (20 mL). Water (10 mL)was then added dropwise with stirring to the mixture, followed by asaturated solution of NaHCO3. The organic layer was washed with wateruntil neutrality and dried over Na₂SO₄. After evaporation of the solventunder reduced pressure, (6R, 12aR)-methyl1,2,3,4-tetrahydro-2-chloroacetyl-1-3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylatewas obtained as an oil which was crystallised from ether to give a solid(0.38 g, m.p.: 233° C.) which was used without further purification inthe next step.

[0697] b) To a stirred suspension of the chloroacetyl intermediate (0.37g) in MeOH (20 mL) was added at room temperature a solution ofmethylamine (33% in EtOH) (0.4 mL) and the resulting mixture was heatedat 50° C. under N₂ for 16 hours. The solvent was removed under reducedpressure and the residue was dissolved in CH₂Cl₂ (50 mL). After washingwith water (3×20 mL), drying over Na₂SO₄ and evaporating to dryness, theresidue was purified by flash chromatography eluting with CH₂Cl₂/MeOH(99/1) and recrystallised from 2-propanol to give the title compound aswhite crystals (0.22 g) m.p.: 302-303° C.

[0698] Analysis for C₂₂H₁₉N₃O₄:

[0699] Calculated: C, 67.86; H, 4.92; N, 10.79;

[0700] Found: C, 67.77; H, 4.92; N, 10.74%.

[0701] [α]_(D) ^(20°)=+71.0° (C=1.00; CHCl₃).

[0702] The following compounds were obtained in a similar manner:

EXAMPLE 79

[0703] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0704] The same two step procedure but starting from isopropylamine andintermediate 54 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 290-293° C.

[0705] Analysis for C₂₄H₂₃N₃O₄:

[0706] Calculated: C, 69.05; H, 5.55; N, 10.07;

[0707] Found: C, 69.06; H, 5.49; N, 10.12%.

[0708] [α]_(D) ^(20 °)=+52.6° (C=1.14; CHCl₃).

EXAMPLE 80

[0709] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-butyl-6-(3,4methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0710] The same two step procedure but starting from butylamine andintermediate 54 gave, after recrystallisation from toluene/hexane, thetitle compound as white crystals m.p.: 209-210° C.

[0711] Analysis for C₂₅H₂₅N₃O₄:

[0712] Calculated: C, 69.59; H, 5.84; N, 9.74;

[0713] Found: C, 69.70; H, 5.93; N, 9.74%.

[0714] [α]_(D) ^(20°)=+50.2° (C=0.53; CHCl₃).

EXAMPLE 81

[0715] (6R,12aR-2,3,6,7,12,12a-Hexahydro-2-isobutyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0716] The same two step procedure but starting from isobutylamine andintermediate 54 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 227-228° C.

[0717] Analysis for C₂₅H₂₅N₃O₄:

[0718] Calculated: C, 69.59; H, 5.84; N, 9.74;

[0719] Found: C, 69.52; H, 5.87; N, 9.74%.

[0720] [α]_(D) ^(20°)=+45° (C=1.04; CHCl₃).

EXAMPLE 82

[0721] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyohenyl)pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0722] The same two step procedure but starting from cyclopentylamineand intermediate 54 gave, after recrystallisation from ether, the titlecompound as white crystals m.p.: 237-239° C.

[0723] Analysis for C₂₆H₂₅N₃O₄:

[0724] Calculated: C, 70.41; H, 5.68; N, 9.47;

[0725] Found: C, 70.13.H, 5.67.N, 9.42%.

[0726] [α]_(D) ^(20°)+=36.6° (C=0.98; CHCl₃).

EXAMPLE 83

[0727] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-2-cyclohexylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0728] The same two step procedure but starting fromcyclohexylmethylamine and the cis isomer of intermediate 56 gave, afterrecrystallisation from 2-propanol the title compound as white crystalsm.p.: 209° C.

[0729] Analysis for C₂₈H₂₉N₃O₄:

[0730] Calculated: C, 71.32; H, 6.20; N, 8.91;

[0731] Found: C, 71.30; H, 6.29; N, 8.74%.

[0732] [α]_(D) ^(20°)=+40.0° (C=0.99; CHCl₃).

EXAMPLE 84

[0733] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0734] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 57 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 204-205° C.

[0735] Analysis for C₂₅H₂₅N₃O₃(0.5H₂O):

[0736] Calculated: C, 70.74; H, 6.17; N, 9.90;

[0737] Found: C, 70.98; H, 6.09; N, 9.92%.

[0738] [α]_(D) ^(20°)+54.1° (C=1.03; CHCl₃).

EXAMPLE 85

[0739] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2butyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0740] The same two step procedure but starting from buylamine andintermediate 57 gave, after recrystallisation from 2propanol, the titlecompound as white crystals m.p.: 183-184° C.

[0741] Analysis for C₂₅H₂₇N₃O₃(0.5H₂O):

[0742] Calculated: C, 70.40; H, 6.62; N, 9.85;

[0743] Found: C, 70.55; H, 6.64; N, 9.92%.

[0744] [α]_(D) ^(20°)=+45.40° (C=1.04; CHCl₃).

EXAMPLE 86

[0745] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0746] The same two step procedure but starting from cyclopentylamineand intermediate 57 gave, after recrystallisation from ether, the titlecompound as white crystals m.p.: 210-211° C.

[0747] Analysis for C₂₆H₂₇N₃O₃:

[0748] Calculated: C, 72.71; H, 6.34; N, 9.78;

[0749] Found: C, 72.53; H, 6.39; N, 9.53%.

[0750] [α]_(D) ^(20°)=+29.8° (C=1.07; CHCl₃).

EXAMPLE 87

[0751] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0752] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 59 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 218-219° C.

[0753] Analysis for C₂₅H₂₄ClN₃O₃ (0.25 H₂O):

[0754] Calculated: C, 66.08; H, 5.43; N, 9.25; Cl, 7.80;

[0755] Found: C, 66.11; H, 5.33; N, 9.03; Cl, 7.74%.

[0756] [α]_(D) ^(20°)=+49.4° (C=1.03; CHCl₃).

EXAMPLE 88

[0757] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-3-chloro-4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0758] The same two step procedure but starting from cyclopentylamineand intermediate 59 gave, after recrystallisation from methanol, thetitle compound as white crystals m.p.: 260-262° C.

[0759] Analysis for C₂₆H₂₆ClN₃O₃:

[0760] Calculated: C, 67.31 ; H, 5.65; Cl, 7.64; N, 9.06;

[0761] Found: C, 66.98; H, 5.67; Cl, 8.06; N, 9.04%.

[0762] [α]_(D) ^(20°)=+27.6° (C=1.05; CHCl₃).

EXAMPLE 89

[0763] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0764] The same two step procedure but starting from methylamine andintermediate 59 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 283-284° C.

[0765] Analysis for C₂₂H₂₀ClN₃O₃:

[0766] Calculated: C, 64.47; H, 4.92; Cl, 8.65; N, 10.25;

[0767] Found: C, 64.49; H, 4.92; C18.33, N, 10.02%.

[0768] [α]_(D) ^(20°)=+61.3° (C=1.00; CHCl₃).

EXAMPLE 90

[0769] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-3-chloro-4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0770] The same two step procedure but starting from isopropylamine andintermediate 59 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 302-304° C.

[0771] Analysis for C₂₄H₂₄ClN₃O₃:

[0772] Calculated: C, 65.83; H, 5.52; N, 9.60;

[0773] Found: C, 65.83; H, 5.57.N, 9.73%.

[0774] [α]_(D) ^(20°)=+39.8° (C=0.95; CHCl₃).

EXAMPLE 91

[0775] (6R,12aR)-2,3,6,7,12,12a-Hexahydo-6-(2,3-dihydrobenzo[b]furan-5-yl-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0776] The same two step procedure but starting from methylamine andintermediate 61 gave, after recrystallisation fromdichloromethane/methanol, the title compound as white crystals m.p.:288-291° C.

[0777] Analysis for C₂₃H₂₁N₃O₃:

[0778] Calculated: C, 71.30; H, 5.46; N, 10.85;

[0779] Found: C, 71.27; H, 5.49; N, 10.96%.

[0780] [α]_(D) ^(20°)=+65.6° (C=0.4; CHCl₃).

EXAMPLE 92

[0781] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(2,3-dihydmbenzo[b]furan-5-yl)-2-methylcyclopropyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0782] The same two step procedure but starting frommethylcyclopropylamine and intermediate 61 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 242-244° C.

[0783] Analysis for C₂₆H₂₅N₃O₃:

[0784] Calculated: C, 73.05; H, 5.89; N, 9.83;

[0785] Found: C, 72.90; H, 5.93; N, 9.98%.

[0786] [α]_(D) ^(20°)=+55.4° (C=0.99; CHCl₃).

EXAMPLE 93

[0787] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-indanyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0788] The same two step procedure but starting from methylamine andintermediate 63 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 262° C.

[0789] Analysis for C₂₄H₂₃N₃O₂:

[0790] Calculated: C, 74.78; H, 6.01; N, 10.90;

[0791] Found: C, 74.65; H, 5.90; N, 10.67%.

[0792] [α]_(D) ^(20°)=+68.6° (C=0.98; CHCl₃).

EXAMPLE 94

[0793] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-5-indanyl)-2-cyclopropylmethyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0794] The same two step procedure but starting fromcyclopropylmethylamine and intermediate 63 gave, after recrystallisationfrom methanol, the title compound as white crystals m.p.: 176° C.

[0795] Analysis for C₂₇H₂₇N₃O₂ (0.25H₂O):

[0796] Calculated: C, 75.41 ; H, 6.45; N, 9.77;

[0797] Found: C, 75.25; H, 6.51; N, 9.75%.

[0798] [α]_(D) ^(20°)=+57.9° (C=1.00; CHCl₃).

EXAMPLE 95

[0799] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0800] To a stirred suspension of Intermediate 73 (12.5 g) in MeOH (400ml) was added at room temperature a solution of methylamine (33% inEtOH) (13.7 ml) and the resulting mixture was heated at 50° C. under N₂for 14 hours. The solvent was removed under reduced pressure and theresidue was dissolved in CH₂Cl₂ (1l). After washing with water (3×500ml), drying over Na₂SO₄ and evaporating to dryness, the white solidobtained was recrystallised from 2-propanol to give the title compoundas white needles (7.5 g).

[0801] mp: 298-300° C.

[0802] [α]_(D) ^(20°)=+71.3° (C=0.55, CHCl₃).

[0803] Elemental analysis (C₂₂H₁₉N₃O₄) calculated: C, 67.86; H, 4.92; N,10.79;

[0804] found: C, 67.79; H, 4.95; N, 10.61%.

EXAMPLE 96

[0805]Cis-2,3,6,7,12,12a-hexahydro-2,10-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0806] The same two step procedure as used to prepare Example 1, butstarting from methylamine and the cis isomer of Intermediate 74, gaveafter recrystallisation from ethanol, the title compound as whitecrystals m.p.: 275° C.

[0807] Analysis for C₂₃H₂₁N₃O₄ (0.4H2O):

[0808] Calculated: C, 67.27; H, 5.35; N, 10.23;

[0809] Found: C, 67.36; H, 5.21; N, 10.31%.

EXAMPLE 97

[0810] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-(3,4-dimethoxybenzyl)-6-3,4-methylenedioxphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0811] The same two step procedure as used to prepare Example 78, butstarting from veratrylamine and intermediate 54 gave, afterrecrystallisation from methanol, the title compound as white crystalsm.p.: 224-226° C.

[0812] Analysis for C₃₀H₂₇N₃O₆:

[0813] Calculated: C, 68.56; H, 5.18; N, 8.00;

[0814] Found: C, 68.80; H, 5.11; N, 8.06%.

[0815] [α]_(D) ^(20°)=+43.9° (C=1.02; CHCl₃).

EXAMPLE 98

[0816]Cis-2,3,6,7,12,12a-hexahydro-6-(4-aminophenyl)-2-butyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0817] To a solution of Example 75 (1.5 g) in methanol (100 mL) wasadded SnCl₂.H₂O (3.06) and the resulting mixture was heated at refluxfor 8 hours. The mixture was cooled to ambient temperature, poured intoice and was adjusted to pH5 with 1N NaOH. The methanol was evaporatedoff and the residue was basified to pH11 with 1 N NaOH and extractedwith EtOAc (2 ×150 mL). After drying over Na₂SO₄ and evaporation ofEtOAc, the resulting yellow powder was purified by radial chromatographyeluting with CH₂Cl₂ to give the title compound as a white powder (550mg) m.p.: 192° C.

[0818] Analysis for C₂₄H₂₆N₄O₂ (1.3 H₂O):

[0819] Calculated: C, 67.68; H, 6.77; N, 13.15;

[0820] Found: C, 67.74; H, 6.68; N, 13.02%.

EXAMPLE 99

[0821]Cis-2,3,6,7,12,12a-hexahydro-6-(4-acetamidophenyl)-2-butyl-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione

[0822] To a solution of Example 98 (0.2 g) in THF (15 mL) was addedtriethylamine (76 μL) and acetyl chloride (39 μL) and the resultingsolution was stirred at room temperature for 2 hours. After evaporationof THF, the resulting residue was taken up in CH₂Cl₂ (100 mL), washedwith water (2×50 mL) and dried over Na₂SO₄. After evaporation of CH₂Cl₂,the resulting solid was recrystallised from MeOH/H₂O to give the titlecompound as a cream powder (120 mg) m.p.: 246° C.

[0823] Analysis for C₂₆H₂₈N₄O₃:

[0824] Calculated: C, 70.25; H, 6.35; N, 12.60;

[0825] Found: C, 69.85; H, 6.38; N, 12.56%.

EXAMPLE 100

[0826]Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylsulfonamidophenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0827] To a solution of Example 98 (0.2 g) in THF (5 mL) was addedtriethylamine (228 μL) and methanesulfonyl chloride (126 μL) and thesolution was heated at reflux for 6 hours. After evaporation of THF, theresidue was taken up in CH₂Cl₂, washed with water and dried over Na₂SO₄.After evaporation of CH₂Cl₂, the residue was purified by radialchromatography eluting with CH₂Cl₂/MeOH (95/5) to give the titlecompound as a brown powder (30 mg) m.p.: 188° C.

[0828] Analysis for C₂₅H₂₈N₄O₄S (0.75 H₂O):

[0829] Calculated: C, 60.77; H, 6.02; N, 11.34;

[0830] Found: C, 60.61; H, 6.02; N, 10.82%.

EXAMPLE 101

[0831] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b]indole-1,4-dione

[0832] The same two step procedure but starting from ammonia andintermediate 54 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 285-290° C.

[0833] Analysis for C₂₁H₁₇N₃O₄:

[0834] Calculated: C, 67.19; H, 4.56; N, 11.19;

[0835] Found: C, 67.30; H, 4.66; N, 11.11%.

[0836] [α]^(20°) _(D)=+88° (C=0.48; pyridine).

EXAMPLE 102

[0837] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4methylenedioxyphenyl)-2-(2-propynyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b] indole-1,4-dione

[0838] The same two step procedure but starting from propargylamine andintermediate 54 gave, after recrystallisation from acetone, the titlecompound as white crystals m.p.: 271° C.

[0839] Analysis for C₂₄H₁₉N₃O₄:

[0840] Calculated: C, 69.72; H, 4.63; N, 10.16;

[0841] Found: C, 69.95; H, 4.66; N, 10.06%.

[0842] [α]^(20°) _(D)=+51.7° (c=0.49; CHCl₃).

EXAMPLE 103

[0843] (6R,12aR)2,3,6,7,12,12a-Hexahydro-2-(3,4-methylendioxybenzyl)-6-t3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b] indole-1,4-dione

[0844] The same two step procedure but starting from piperonylamine andintermediate 54 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 204-206° C.

[0845] Analysis for C₂₉H₂₃N₃O₆:

[0846] Calculated: C, 68.36; H, 4.55; N, 8.25;

[0847] Found: C, 68.25; H, 4.49; N, 8.41.

[0848] [α]^(20°) _(D)=+43° (c=1.01; CHCl₃).

EXAMPLE 104

[0849] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-(3,4-dimethoxyphenethyl)-6-3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b]indole-1,4-dione

[0850] The same two step procedure but starting from3,4-dimethoxyphenethylamine and intermediate 54 gave, afterrecrystallisation from dichloromethane/ether, the title compound aswhite crystals m.p.: 265-266° C.

[0851] Analysis for C₃₁H₂₉N₃O₆:

[0852] Calculated: C, 69.00; H, 5,42; N, 7.79;

[0853] Found: C, 68.68; H, 5.35; N, 7.78%.

[0854] [α]^(20°) _(D)=+38.3° (c=1.12; CHCl₃).

EXAMPLE 105

[0855] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-furfuryl-6-3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b]indole-1,4-dione

[0856] The same two step procedure but starting from furfurylamine andintermediate 54 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 219° C.

[0857] Analysis for C₂₆H₂₁N₃O₅:

[0858] Calculated: C, 68.56; H, 4.65; N, 9.23;

[0859] Found: C, 68.16; H, 4.63; N, 9.15%.

[0860] [α]^(20°) _(D)=+58.1° (c=1.2; CHCl₃)

EXAMPLE 106

[0861] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-3,4-methylenedioxyphenyl)-2(2-thienylmethyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b]indole-1,4-ione

[0862] The same two step procedure but starting from2-thiophenemethylamine and intermediate 54 gave, after recrystallisationfrom methanol/water, the title compound as white crystals m.p.: 155-157°C.

[0863] Analysis for C₂₆H₂₁N₃O₄S:

[0864] Calculated: C, 66.23; H, 4.49; N, 8.91; S, 6.8;

[0865] Found: C, 66.13; H, 4.54; N, 9.12; S, 6.78%.

[0866] [α]^(20°) _(D)=+70.4° (c=1.03; CHCl₃).

EXAMPLE 107

[0867] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(4-methoxyphenyl)-2-methyl-pyrazino

[0868] [2′,1′:6,1]pyrido [3,4-b]indole-1,4-dione

[0869] The same two step procedure but starting from methylamine andintermediate 57 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 285-288° C.

[0870] Analysis for C₂₂H₂₁N₃O₃:

[0871] Calculated: C, 70.38; H, 5.64; N, 11.19;

[0872] Found: C, 70.31; H, 5.69; N, 11.29%.

[0873] [α]^(20°) _(D)=+59° (c=1.19; CHCl₃).

EXAMPLE 108

[0874] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-ethyl-6-(4-methoxyphenyl)-pyrazino [2′,1′:6,1]pyrido [3,4-b] indole-1,4-dione

[0875] The same two step procedure but starting from ethylamine andintermediate 57 gave, after recrystallisation from methanol, the titlecompound as white crystals m.p.: 277° C.

[0876] Analysis for C₂₃H₂₃N₃O₃:

[0877] Calculated: C, 70.93; H, 5.95; N, 10.79;

[0878] Found: C, 70.90; H, 5.96; N, 10.54%.

[0879] [α]^(20°) _(D)=+52° (c=1.28; CHCl₃).

EXAMPLE 109

[0880] (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(7-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl))-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0881] The same two step procedure but starting from intermediate 75 andmethylamine gave, after recrystallisation from ethanol, the titlecompound as white crystals m.p.: 285-288° C.

[0882] Analysis for C₂₄H₂₄N₄O₃ (0.5 H₂O):

[0883] Calculated: C, 67.75; H, 5.92; N, 13.17;

[0884] Found: C, 68.02; H, 6.00; N, 13.18%.

[0885] [α]^(20°) _(D)=+71.7° (c=1, pyridine).

EXAMPLE 110

[0886] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-5-(N-benzylindolinyl))-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0887] The same two step procedure but starting from intermediate 77 andmethylamine gave, after recrystallisation from dichloromethanelmethanol,the title compound as white crystals m.p.: 223-225° C.

[0888] Analysis for C₃₀H₂₈N₄O₂:

[0889] Calculated: C, 75.61; H, 5.92; N, 11.76;

[0890] Found: C, 75.2; H, 5.78; N, 11.67%.

[0891] [α]^(20°) _(D)=+20.4° (c=0.5, CHCl₃).

EXAMPLE 111

[0892] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-indolinyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0893] A solution of Example 110 (1.05 g, 2.2 mmol) in methanol (100 mL)was hydrogenated in the presence of 10% Pd-C (100 mg) for 48 hours atroom temperature. After removal of the catalyst, the solvent wasevaporated in vacuo to leave a residue which was purified by flashchromatography eluting with dichloromethanelmethanol : 96/4. The solidobtained was recrystallised from dichloromethane/methanol to give thetitle compound (300 mg) as white crystals m.p.: 240° C.

[0894] Analysis for C₂₃H₂₂N₄O₂ (0.5 H₂O):

[0895] Calculated: C, 69.86; H, 5.86; N, 14.17;

[0896] Found: C, 70.13; H, 5.77; N, 14.06%.

[0897] [α]^(20°) _(D)=+55.9° (c=1.18; pyridine).

EXAMPLE 112

[0898]Cis-2,3,6,7,12,12a-hexahydro-6-(4-ethylphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0899] The same two step procedure but starting from methylamine and thecis isomer of intermediate 42 gave, after recrystallisation frommethanol, the title compound was white crystals m.p.: 254° C.

[0900] Analysis for C₂₃H₂₃N₃O₂ (0.25 H₂O):

[0901] Calculated: C, 73.09; H, 6.27; N, 11.12;

[0902] Found: C, 73.03; H, 6.18; N, 11.36%.

EXAMPLE 113

[0903] (6RP12aR)-2,3,6,7,12,12a-Hexahydro-6-(4-carbomethoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0904] The same two step procedure but starting from intermediate 78(cis isomer) and methylamine gave, after recrystallisation frommethanol, the title compound as white crystals m.p.: 308-312° C.

[0905] Analysis for C₂₃H₂₁N₃O₄:

[0906] Calculated: C, 68.47; H, 5.25; N, 10.42;

[0907] Found: C, 68.76; H, 5.18; N, 10.35%.

[0908] [α]^(20°) _(D)+97.7° (c=1, pyridine).

EXAMPLE 114

[0909] (5aR, 12R,14aR)-1,2,3,5a,6,11,12,14a-Octahydro-12-3,4-methylenedioxyphenyl)-pyrrolo[1″2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5-1,4-dione

[0910] A solution of intermediate 80 (0.7 g, 1.2 mmol) in a mixture ofmethano/THF (80/40 mL) was hydrogenated in the presence of 10% PdC (75mg) for 48 hours at 40° C. After removal of the catalyst, the solventwas evaporated in vacuo to leave a residue, which was purified by flashchromatography eluting with dichloromethane/methanol: 98/2. The whitesolid obtained was recrystallised from methanol to give the titlecompound (180 mg) as white crystals m.p.: 284-287° C.

[0911] Analysis for C₂₄H₂₁N₃O₄:

[0912] Calculated: C, 69.39; H, 5.10; N, 10.11;

[0913] Found: C, 69.47; H, 5.11; N, 9.97%.

[0914] [α]^(20°) _(D)=+21.7° (c=0.64, CHCl₃).

EXAMPLE 115

[0915] (5aR, 12R,14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-3,4-methylenedioxyphenyl)-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5-1,4-dione

[0916] A solution of intermediate 81 (0.8 g, 1.37 mmol) in methanol (40mL) was hydrogenated in the presence of 10% Pd-C (100 mg) for 5 h at 45°C. After removal of the catalyst the solvent was evaporated in vacuo toleave a residue, which was purified by flash chromatography eluting withdichloromethanelmethanol: 98/2. The solid obtained was recrystallisedfrom methanol to give the title compound (300 mg) as white crystalsm.p.: 302-304° C.

[0917] Analysis for C₂₄H₂₁N₃O₄:

[0918] Calculated: C, 69.39; H, 5.10; N, 10.11;

[0919] Found: C, 69.35; H, 5.11; N, 10.10%.

[0920] [α]^(20°) _(D)=+106.8° (c=1.08, CHCl₃).

EXAMPLE 116

[0921] (3R, 6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0922] To a stirred solution of intermediate 82 (0.15 g, 0.34 mmol) inTHF (15 mL) was added at room temperature a solution of methylamine (33%in EtOH) (0.32 mL) and the resulting solution was heated at reflux underN₂ for 24 hours. The solvent was removed under reduced pressure and theresidue was dissolved in CH₂Cl₂ (25 mL). After washing with water (2×20mL), drying over Na₂SO₄ and evaporating to dryness, the crude productwas purified by flash chromatography eluting withdichloromethane/methanol 99/1. The white solid obtained wasrecrystallised from methanol to give the title compound as whitecrystals (80 mg) m.p.: 219-220° C.

[0923] Analysis for C₂₃H₂₁N₃O₄:

[0924] Calculated: C, 68.47; H, 5.25; N, 10.42;

[0925] Found: C, 68.39; H, 5.21; N, 10.42%.

[0926] [α]^(20°) _(D)=+89.6° (c=1; CHCl₃).

EXAMPLE 117

[0927] (3S, 6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0928] To a stirred solution of intermediate 83 (0.3 g, 0.68 mmol) inTHF (30 mL) was added at room temperature a solution of methylamine (33%in EtOH) (0.68 mL) and the resulting solution was treated at refluxunder N₂ for 6 days. The solvent was removed under reduced pressure andthe residue was dissolved in CH₂Cl₂ (50 mL). After washing with water(2,25 mL), drying over Na₂SO₄ and evaporating to dryness, the crudeproduct was purified by flash chromatography eluting withdichloromethane/methanol 99/1. The oily residue obtained wascrystallised from methanol to give the title compound as white crystals(40 mg) m.p.: 307-309° C.

[0929] Analysis for C₂₃H₂₁N₃O₄:

[0930] Calculated: C, 68.47; H, 5.25; N, 10.42;

[0931] Found: C, 68.35; H, 5.33; N, 10.42%.

[0932] [α]^(20°) _(D)=+65.2° (c=1.15; CHCl₃).

EXAMPLE 118

[0933] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-dihydroxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0934] A solution of intermediate 86 (0.75 g; 1.34 mmol) in a mixture ofethano/THF (70/30 mL) was hydrogenated in the presence of 10% Pd-C (75mg) for 24 h at room temperature. After removal of the catalyst, thesolvent was evaporated in vacuo to leave a white solid which wasrecrystallisated from methanol to give the title compound (0.35 g) aswhite crystals m.p.: 224-226° C.

[0935] Analysis for C₂₁H₁₉N₃O₄:

[0936] Calculated: C, 66.83; H, 5.07; N, 11.13;

[0937] Found: C, 66.58; H, 5.01; N, 11.04%.

[0938] [α]^(20°) _(D)=+58.4° (c=1.04; pyridine).

EXAMPLE 119

[0939] (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(5-(2-methylisoindolinyl))pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione

[0940] The same two steps procedure but starting from intermediate 87and methylamine gave a crude oil which was purified by flashchromatography eluting with dichloromethane/methanol/triethylamine:92/8/0.1%. The solid obtained was recrystallized from isopropanol/propylether/water to give the title compound (20 mg) as off-white crystalsm.p.: 236° C.

[0941] Analysis for C₂₄H₂₄N₄O₂ (2.68 H₂O)

[0942] Calculated: C, 64.23; H, 6.59; N, 12.48;

[0943] Found: C, 64.21; H, 6.43; N, 12.02%.

[0944] [α]^(20°) _(D) =−61.1° (c=0.5; CH₃OH).

EXAMPLE 120

[0945] Compounds of formula (I) have been included in pharmacyformulations and details of such formulations are given below.

[0946] Tablets for Oral Administration

[0947] A. Direct Compression 1. mg/tablet Active ingredient 50.0Crospovidone USNF 8.0 Magnesium Stearate Ph Eur 1.0 Anhydrous Lactose141.0

[0948] The active ingredient was sieved and blended with the excipients.The resultant mix was compressed into tablets. 2. mg/tablet Activeingredient 50.0 Colloidal Silicon Dioxide 0.5 Crospovidone 8.0 SodiumLauryl Sulphate 1.0 Magnesium Stearate Ph Eur 1.0 MicrocrystallineCellulose USNF 139.5

[0949] The active ingredient was sieved and blended with the excipients.The resultant mix was compressed into tablets.

[0950] B. Wet Granulation 1. mg/tablet Active ingredient 50.0 Polyvinylpyrollidone 150.0 Polyethylene glycol 50.0 Polysorbate 80 10.0 MagnesiumStearate Ph Eur 2.5 Croscarmellose Sodium 25.0 Colloidal Silicon Dioxide2.5 Microcrystalline Cellulose USNF 210.0

[0951] The polyvinyl pyrollidone, polyethylene glycol and polysorbate 80were dissolved in water. The resultant solution was used to granulatethe active ingredient. After drying the granules were screened, thenextruded at elevated temperatures and pressures. The extrudate wasmilled and for screened then was blended with the microcrystallinecellulose, croscarmellose sodium, colloidal silicon dioxide andmagnesium stearate. The resultant mix was compressed into tablets. 2.mg/tablet Active ingredient 50.0 Polysorbate 80 3.0 Lactose Ph Eur 178.0Starch BP 45.0 Pregelatinised Maize Starch BP 22.5 Magnesium Stearate BP1.5

[0952] The active ingredient was sieved and blended with the lactose,starch and pregelatinised maize starch. The polysorbate 80 was dissolvedin purified water. Suitable volumes of the polysorbate 80 solution wereadded and the powders were granulated. After drying, the granules werescreened and blended with the magnesium stearate. The granules were thencompressed into tablets.

[0953] Tablets of other strengths may be prepared by altering the ratioof active ingredient to the other excipients.

[0954] Film Coated Tablets

[0955] The aforementioned tablet formulations were film coated. CoatingSuspension % w/w Opadry white†   13.2   Purified water Ph Eur to 100.0*

[0956] Opadry white is a proprietary material obtainable from ColorconLimited, UK which contains hydroxypropyl methylcellulose, titaniumdioxide and triacetin.

[0957] The tablets were film coated using the coating suspension inconventional film coating equipment.

[0958] Capsules 1. mg/capsule Active ingredient 50.0 Lactose 148.5Polyvinyl pyrollidone 100.0 Magnesium Stearate 1.5

[0959] The active ingredient was sieved and blended with the excipients.The mix was filled into size No. 1 hard gelatin capsules using suitableequipment. 2. mg/capsule Active ingredient 50.0 MicrocrystallineCellulose 233.5 Sodium Lauryl Sulphate 3.0 Crospovidone 12.0 MagnesiumStearate 1.5

[0960] The active ingredient was sieved and blended with the excipients.The mix was filled into size No. 1 hard gelatin capsules using suitableequipment.

[0961] Other doses may be prepared by altering the ratio of activeingredient to excipient, the fill weight and if necessary changing thecapsule size. 3. mg/capsule Active ingredient 50.0  Labrafil M1944CS to1.0 ml

[0962] The active ingredient was sieved and blended with the Labrafil.The suspension was filled into soft gelatin capsules using appropriateequipment.

EXAMPLE 121

[0963] Inhibitory Effect on cGMP-PDE

[0964] cGMP-PDE activity of compounds of the present invention wasmeasured using a one-step assay adapted from Wells at al. (Wells, J. N.,Baird, C. E., Wu, Y. J. and Hardman, J. G., Biochim. Biophys. Acta 384,430 (1975)). The reaction medium contained 50 mM Tris-HCl, pH 7.5, 5 mMMg-acetate, 250; μg/ml 540 -Nucieotidase, 1 mM EGTA and 0.15 μM8[H³]-cGMP. The enzyme used was a human recombinant PDE V (ICOS, SeattleUSA).

[0965] Compounds of the invention were dissolved in DMSO finally presentat 2% in the assay. The incubation time was 30 minutes during which thetotal substrate conversion did not exceed 30%.

[0966] The IC₅₀ values for the compounds examined were determined fromconcentration-response curves using typically concentrations rangingfrom 10 nM to 101 μM. Tests against other PDE enzymes using standardmethodology also showed that compounds of the invention are highlyselective for the cGMP specific PDE enzyme.

[0967] -cGMP Level Measurements

[0968] Rat aortic smooth muscle cells (RSMC) prepared according toChamley et al. in Cell Tissue Res. 177, 503-522 (1977) were used betweenthe 10th and 25th passage at confluence in 24-well culture dishes.Culture media was aspirated and replaced with PBS (0.5 ml) containingthe compound tested at the appropriate concentration. After 30 minutesat 37° C., particulates guanylate cyclase was stimulated by addition ofANF (100 nM) for 10 minutes. At the end of incubation, the medium waswithdrawn and two extractions were performed by addition of 65% ethanol(0.25 ml). The two ethanolic extracts were pooled and evaporated untildryness, using a Speed-vac system. c-GMP was measured after acetylationby scintillation proximity immunoassay (AMERSHAM).

[0969] The compounds according to the present invention were typicallyfound to exhibit an IC₅₀ value of less than 500 nM, and an EC₅₀ value ofless than 5. In vitro test data for representative compounds of theinvention is given in following Table 1: TABLE 1 Example No. IC₅₀ nMEC₅₀ μM 12 10 0.15 36 <10 0.5 52 20 0.8 63 30 0.35 79 <10 0.15 82 20 0.584 10 0.4 89 10 <0.1 95 2 0.2 101 10 0.3 115 <10 0.4

EXAMPLE 122

[0970] -Antihypertensive Activity in Rats

[0971] The hypotensive effects of compounds according to the inventionas identified in table 2 studied in conscious spontaneously hypertensiverats (SHR). The compounds were administered orally at a dose of 5 mg/kgin a mixture of 5% DMF and 95% olive oil. Blood pressure was measuredfrom a catheter inserted in the carotid artery and recorded for 5 hoursafter administration. The results are expressed as Area Under the Curve(AUC from 0 to 5 hours, mmHg.hour) of the fall in blood pressure overtime.

[0972] In Vivo Results Example No. AUC PO (mmHg.h) 36 99 63 95 79 171 82111 84 77 89 117 95 135 101 136

1. A compound of formula (I)

and salts and solvates thereof, in which: R^(o) represents hydrogen,halogen or C₁₋₆ alkyl; R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆ alkynyl, haloC₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₃alkyl,arylC₁₋₃alkyl or heteroarylC₁₋₃alkyl; R² represents an optionallysubstituted monocyclic aromatic ring selected from benzene, thiophene,furan and pyridine or an optionally substituted bicyclic ring

attached to the rest of the molecule via one of the benzene ring carbonatoms and wherein the fused ring A is a 5- or 6-membered ring which maybe saturated or partially or fully unsaturated and comprises carbonatoms and optionally one or two heteroatoms selected from oxygen,sulphur and nitrogen; and R³ represents hydrogen or c₁₋₃ alkyl, or R¹and r³ together represent a 3- or 4-membered alkyl or alkenyl chain. 2.A compound of formula (Ia)

and salts and solvates thereof, in which: R^(o) represents hydrogen,halogen or C₁₋₆ alkyl; R¹ represents hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₃alkyl, arylC₁₋₃alkyl orheteroarylC₁₋₃alkyl; and R² represents an optionally substitutedmonocyclic aromatic ring selected from benzene, thiophene, furan andpyridine or an optionally substituted bicyclic ring

attached to the rest of the molecule via one of the benzene ring carbonatoms and wherein the fused ring A is a 5- or 6-membered ring which maybe saturated or partially or fully unsaturated and comprises carbonatoms and optionally one or two heteroatoms selected from oxygen,sulphur and nitrogen.
 3. A compound according to claim 1 or 2, whereinR^(o) represents hydrogen.
 4. A compound according to any of claims 1 to3, wherein R¹ represents hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylmethyl, pyridylC₁₋₃alkyl, furylC₁₋₃alkylor optionally substituted benzyl.
 5. A compound according to any ofclaims 1 to 3, wherein R¹ and R³ together represent a 3-membered alkylchain.
 6. A compound according to any of claims 1 to 4, wherein R³represents hydrogen.
 7. A compound according to any of claims 1 to 6,wherein R² represents an optionally substituted benzene, thiophene,furan, pyridine or naphthalene ring or an optionally substitutedbicyclic ring

where n is 1 or 2 and X and Y are each CH₂ or O.
 8. A cis isomer offormula (I) represented by formula (Ib)

and mixtures thereof with its cis optical enantiomer, including racemicmixtures, and salts and solvates of these compounds in which R^(o) ishydrogen or halogen and R¹, R² and R³ are as defined in any precedingclaim. 9.Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;Cis-2,3,6,7,12,12a-hexahydro-6(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione;(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3chloro-4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4b]indole-1,4-dione;(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido [3,4-b] indole-1,4-dione; (5aR, 12R,14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-(3,4-methylenedioxyphenyl)pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5-1,4-dione;and physiologically acceptable salts and solvates thereof.
 10. (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;and physiologically acceptable salts and solvates thereof.
 11. Acompound according to any of claims 1 to 10, for use in the treatment ofstable, unstable and variant angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, congestive heartfailure, renal failure, atherosclerosis, conditions of reduced bloodvessel patency, peripheral vascular disease, vascular disordersinflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma or diseases characterised bydisorders of gut motility.
 12. Use of a compound according to any ofclaims 1 to 10, for the manufacture of a medicament for the treatment ofstable, unstable and variant angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, congestive heartfailure, renal failure, atherosclerosis, conditions of reduced bloodvessel patency, peripheral vascular disease, vascular disorders,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma or diseases characterised bydisorders of gut motility.
 13. A method of treating stable, unstable andvariant angina, hypertension, pulmonary hypertension, chronicobstructive pulmonary disease, congestive heart failure, renal failure,atherosclerosis, conditions of reduced blood vessel patency, peripheralvascular disease, vascular disorders, inflammatory diseases, stroke,bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucomaor diseases characterised by disorders of gut motility, in a human ornon-human animal body, which method comprises administering to said bodya therapeutically effective amount of a compound according to any ofclaims 1 to
 10. 14. A pharmaceutical composition comprising a compoundof the according to any of claims 1 to 10, together with apharmaceutically acceptable diluent or carrier therefor.
 15. A processof preparing a pharmaceutical composition comprising a compoundaccording to any of claims 1 to 10, which process comprises mixing saidcompound together with a pharmaceutically acceptable diluent or carriertherefor.
 16. A process of preparing a compound of formula (I), whichprocess comprises: a process (A) for preparing a compound of formula(I), wherein R³ represents hydrogen which process (A) comprises treatinga compound of formula (II)

in which Alk represents Cl-alkyl and Hal is a halogen atom, with aprimary amine R¹NH₂; or a process (B) for preparing a compound offormula (I), wherein R¹ and R³ together represent a 3- or 4-memberedalkyl or alkenyl chain, which process (B) comprises cyclisation of acompound of formula (VIII)

wherein Alk represents C₁₋₆alkyl and R¹ and R³ together represent a 3-or 4-membered chain both as defined above; or a process (C) forpreparing a compound of formula (I) wherein R³ represents C₁₋₃alkyl,which process (C) comprises cyclisation of a compound of formula (X)

wherein Alk represents Ca₁₋₆alkyl and R⁵ represents C₂₋₅alkyl,substituted at C₁ by a halogen atom; or process (A), (B) or (C) ashereinbefore described followed by i) an interconversion step; and/oreither ii) salt formation; or p1 iii) solvate formation.
 17. Compoundsof formulae (II), (III), (V), (VI), (VII), (VIII) and (X), with theexception for compounds (III), (V), (VI) and (VII) wherein R^(o) ishydrogen, R² is phenyl and Alk is methyl.